The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index; 28 of the 45 sources its claims cite were checked for support.
GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis
Open accessAbstract
Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.
Overview
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Written from the paper’s full text.
TL;DR
GPR146 deficiency lowers plasma cholesterol and triglycerides by reducing hepatic ERK1/2–SREBP2 signaling and VLDL secretion, and this lipid-lowering effect does not require LDL receptor activity. In LDLR-deficient mice, GPR146 depletion markedly reduces atherosclerotic lesions, by ~90% in males and ~70% in females on western diet.
Key findings
- GPR146 depletion reduced plasma total cholesterol by 20% in male and 25% in female chow-fed mice; FPLC showed HDL-C, LDL-C, and VLDL-C reductions of ~15%, ~35%, and ~25%, respectively, with plasma TG also reduced.
- Hepatocyte-specific GPR146 depletion reduced plasma TC by ~20%, and GPR146 loss reduced hepatic VLDL secretion; in Huh7 cells, CRISPR depletion of GPR146 led to 30% less secreted APOB100.
- GPR146 deficiency decreased hepatic pERK1/2 and mature SREBP2 upon feeding or 6-hour fasting; the MEK inhibitor PD0325901 reduced plasma TC by ~22% in wild-type mice but had no additional effect in Gpr146−/− mice.
- In Ldlr−/− mice, GPR146 depletion reduced plasma TC by ~30% on chow in both sexes, by ~60% in males and ~35% in females on western diet, and reduced aortic atherosclerotic lesion area by ~90% in males and ~70% in females after 16 weeks of western diet.
Methods
- Human genetic evidence used eQTL analysis of rs1997243 and GPR146 expression in 2,116 BIOS blood samples; mouse models included CRISPR/Cas9-generated whole-body and floxed Gpr146 alleles, liver- and adipocyte-specific knockouts, and crosses to Ldlr−/− mice.
- In vivo analyses included plasma lipid assays, FPLC, Poloxamer-407 hepatic VLDL secretion assays, fecal and hepatic lipid measurements, and en face Oil Red O quantification of aortic atherosclerotic lesions; acute hepatic GPR146 knockdown used AAV8-shRNA in adult Ldlr−/− mice.
- In vitro work used Huh7, HepG2, AML12, and HEK293T cells with CRISPR knockout, overexpression, APOB100 ELISA, LDL uptake, immunoblotting, qPCR, and microarray/GSEA (GEO: GSE139082); statistics used t tests or one-way ANOVA with Tukey post hoc, p < 0.05.
Limitations
- The paper states that the detailed signaling cascade by which GPR146 regulates ERK1/2 remains under investigation, the natural ligand is unknown, and GPR146 may act directly or indirectly through other growth factor/hormone pathways.
- The paper notes that other GPR146 downstream pathways may modulate plasma TC during prolonged 16-hour fasting, when ERK1/2 and SREBP2 activities were unchanged.
- Evident from the text: human evidence is limited to genetic association/eQTL data, with no human intervention; mechanistic and atherosclerosis findings rely on mouse models and cell lines, and some supporting EGR gene expression data are described as “data not shown.”
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Claims the paper makes
87 Own result · 39 Own interpretation · 14 Own method · 9 Partly supported · 4 No full text of the sources · 3 Supported so far · 3 Not checked yet · 3 No basis given · 1 Couldn’t confirm · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“GPR146, a susceptible gene associated with plasma total cholesterol (TC), LDL-C and high density lipoprotein cholesterol (HDL-C) levels”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
What the sources say
- Could not verifycites Klarin et al., 2018 sourceExperimental — accuracy not yet measured
The Results passages on lipid associations discuss other genes, including PDE3B, but do not identify GPR146 as associated with total cholesterol, LDL-C, or HDL-C. Searches for “GPR146” and “GPR146 total cholesterol LDL-C HDL-C” found no passage addressing that gene; page numbers were not available in our copy. (LLM, conf=0.72)
- Could not verifycites Liu et al., 2017 sourceExperimental — accuracy not yet measured
The paper’s Abstract reports variants associated with TC, LDL-C and HDL-C, but the passages retrieved from our copy do not identify GPR146 as an associated gene. Searches for “GPR146” and “G protein-coupled receptor 146” did not find a passage addressing the claimed associations. (LLM, conf=0.70)
- Could not verifycites Teslovich et al., 2010 sourceExperimental — accuracy not yet measured
The Biological Relevance of GWAS Loci section links a locus associated with TC, LDL-C, and HDL-C to PPP1R3B, but does not mention GPR146. Searches for GPR146 and for its proposed association with all three lipid measures found no passage in our copy that addresses the claim. (LLM, conf=0.72)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The alternative allele of a common variant (rs1997243-G), located 11-kb upstream of GPR146, has been shown to be associated with increased plasma TC, HDL-C and LDL-C levels in humans (Klarin et al., 2018; Liu et al., 2017; Willer et al., 2013)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
What the sources say
- Could not verifycites Klarin et al., 2018 sourceExperimental — accuracy not yet measured
The Results section on lipid genetic associations discusses other variants, but the passages from our copy do not identify rs1997243-G or GPR146. Searches for both terms and for the claimed upstream location and lipid associations found no passage establishing this specific claim; the other papers cited in the sentence were not assessed. (LLM, conf=0.73)
- Could not verifycites Liu et al., 2017 sourceExperimental — accuracy not yet measured
The paper’s Abstract reports associations between genetic variants and plasma lipids, but the passages from our copy do not identify rs1997243 or GPR146. Searches for both terms found no passage establishing the variant’s location, allele direction, or association with increased TC, HDL-C, and LDL-C; pages are not provided in our copy. (LLM, conf=0.74)
- Partly supportedcites Willer et al., 2013 sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) reports that variants near human GPR146 are associated with total cholesterol levels. It does not identify rs1997243-G, place it 11 kb upstream, establish the direction of its effect, or report increased HDL-C and LDL-C for that allele. (LLM, conf=0.85)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Patients with homozygous familial hypercholesterolemia (HoFH, LDLR mutations in both alleles) have markedly diminished response to both therapies as their lipid-lowering effects require upregulation of LDLR activity (Cuchel et al., 2014; Defesche et al., 2017).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
What the sources say
- Partly supportedcites Cuchel et al., 2014 sourceExperimental — accuracy not yet measured
The Pharmacotherapy section (page not specified) reports only modest LDL-C reductions of 10–25% with high-dose statins in most HoFH patients. Future options (page not specified) reports smaller evolocumab reductions in HoFH than in HeFH, and Figure 9 describes PCSK9 inhibitors as increasing LDL-receptor recycling. But the paper also says statins work even in receptor-negative patients, so it does not support the claim that both therapies require LDLR upregulation; it also notes that some HoFH cases involve genes other than LDLR. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Defesche et al., 2017 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Human genetic studies have unequivocally established GPR146 as a susceptible gene regulating plasma cholesterol levels.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
What the sources say
- Could not verifycites Klarin et al., 2018 sourceExperimental — accuracy not yet measured
The Discussion describes genetic loci associated with blood lipids, but the passages do not identify GPR146 as one of them or establish that it regulates plasma cholesterol. Searches for “GPR146” and “G protein-coupled receptor 146” found no passage addressing that gene. (LLM, conf=0.72)
- Could not verifycites Liu et al., 2017 sourceExperimental — accuracy not yet measured
The Abstract reports human genetic associations with plasma lipids, but the passages retrieved do not identify GPR146 or establish its role in regulating cholesterol. Searches for “GPR146” and “G protein-coupled receptor 146 cholesterol genetic association” found no passage addressing that gene. (LLM, conf=0.72)
- Partly supportedcites Willer et al., 2013 sourceExperimental — accuracy not yet measured
The Discussion reports that variants near human GPR146 are associated with total cholesterol levels. It also says that establishing which genes cause the associations will be challenging and describes GPR146 inhibition as speculative. The study therefore supports a genetic association near GPR146, not the claim that GPR146 has been unequivocally established as a gene regulating cholesterol. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Substantial evidence supports the conclusion that hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding, indicating the existence of feeding-responsive signaling pathways upregulating hepatic cholesterol synthesis in the presence of dietary nutrition (Horton et al., 1998; Liang et al., 2002; Matsuda et al., 2001; Slakey et al., 1972).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Supportedcites Horton et al., 1998 source
The Results report that fasting markedly reduced nuclear SREBP-2 and that refeeding restored it to nonfasted levels. The Discussion links this pattern to cholesterol-synthesis gene expression, supporting a feeding-responsive increase. The increase was a return to baseline, not an overshoot above it. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Liang et al., 2002 source
- Supportedcites Matsuda et al., 2001 source
The Results (page not provided) report that fasting reduced hepatic SREBP-2 and lipid-synthesis target-gene mRNAs in mice, while refeeding raised several cholesterol-synthesis enzyme mRNAs above baseline. This supports the attributed conclusion that feeding-responsive regulation upregulates hepatic cholesterol synthesis. (LLM, conf=0.86)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“depletion of GPR146 in Huh7 cells has no effect on uptake of LDL particles”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“No significant difference was observed in dynamic changes of plasma TG levels between Gpr146+/+ and Gpr146−/− mice (Figure S2K).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PD0325901 significantly reduced plasma TC levels by ~22% in Gpr146+/+ (C57BL/6) mice (vehicle vs PD: 66.4 ± 5.4 mg/dl vs 51.8 ± 7.8 mg/dl)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“no difference in plasma TC levels was observed between Adipoq-Cre+ Gpr146fl/fl mice and control littermates (Figure S2O and S2P), suggesting that adipocyte-resident GPR146 does not regulate circulating cholesterol levels”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“CRISPR/Cas9-mediated depletion of GPR146 in Huh7 cells led to 30% less secreted APOB100 levels than that in control cells”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HDL-C, LDL-C and very low density lipoprotein cholesterol (VLDL-C) were reduced by ~15%, ~35% and ~25%, respectively”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HDL-C, LDL-C and very low density lipoprotein cholesterol (VLDL-C) were reduced by ~15%, ~35% and ~25%, respectively”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“rs1997243-G is associated with an increased expression of GPR146 in human blood (analyzed in 2,116 blood samples from the Biobank-based integrative omics study (BIOS))”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaincorrelationaln = 2,116- Asserted: passes — The authors put it forward as true.
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In the paper
“No significant difference was found in TC/TG contents of fecal excretions between Gpr146−/− and Gpr146+/+ littermates fed either chow or HFD for 3 weeks”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Protein levels of SREBP2 target genes, such as Hmgcr, Hmgcs1 and Ldlr, were also significantly reduced in the absence of GPR146”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced plasma TC levels in Gpr146−/− mice also occurred upon 6-hour fasting or 6-hour refeeding following a 16-hour fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA levels of known genes that are involved in regulation of hepatic VLDL assembly and secretion, such as Mttp, Apob, Dgat1, Dgat2 and Sort1, were unchanged in GPR146-deficient mice compared to wild type littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 depletion also led to significantly reduced plasma TG levels in both male and female mice fed chow (Figure S1K and S1L) or HFD (Figure S1M)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Promotes Plasma TG Levels
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This variant is in strong linkage disequilibrium (r2= 0.989 in non-Finnish European population) with a coding variant of GPR146 (rs11761941: p.Gly11Glu)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“we used CRISPR/Cas9 to deplete ERK1 and ERK2 individually or ERK1/2 together in HepG2 cells and found both the basal and serum stimulated expression levels of SREBP2, HMGCR and LDLR were significantly reduced in the absence of ERK2, but not ERK1”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“GPR146 deficiency reduced plasma TC levels by ~20% in mice fed chow and by ~30% in mice fed WD”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the total circulating APOB100 levels were lower in Gpr146−/− mice compared to Gpr146+/+ littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“all of which revealed that the cholesterol biosynthesis pathway was significantly downregulated in liver of GPR146-deficient mice compared to wild-type littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“hepatic VLDL-TG/TC secretion rates were significantly reduced in Alb-Cre+ Gpr146fl/fl mice compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“protein levels of mature SREBP2 were also reduced in the presence of MEK inhibitor compared to DMSO control”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“plasma TC levels were significantly reduced by 20% in male and by 25% in female Gpr146−/− mice fed chow compared to Gpr146+/+ littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Serum treatment after starvation induced transcriptional upregulation of SREBP2 and its classic downstream genes HMGCR and LDLR in human hepatoma HepG2, Huh7 and mouse hepatocyte AML12 cells”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146’s molecular function reveal that it promotes ERK1/2 signaling in hepatocytes upon feeding or short period of fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while it was greatly attenuated after blocking MEK1/ERK1/2 pathway using the well-characterized MEK1 inhibitor PD0325901(PD)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the extracellular signal-regulated kinases (ERK1/2) activities were decreased in livers from both male and female Gpr146−/− mice compared to Gpr146+/+ littermates upon feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Gpr146 mRNA was highly expressed in liver and epidydimal white adipose tissue of chow-fed wild-type (Gpr146+/+) mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146-deficient mice fed a high-fat diet (HFD) exhibited a ~29% reduction of plasma TC levels compared to control mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while no significant difference was observed in mice after a prolonged 16-hour fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Quantitative real-time PCR (qRT-PCR) revealed no difference in hepatic expression of HDL biosynthetic genes Apoa1 and Abca1 between Gpr146−/− and Gpr146+/+ control mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“recombinant overexpression of GPR146 in HepG2 and Huh7 cells promoted the expression levels of both HMGCR and LDLR compared to GFP control upon serum stimulation”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“recombinantly overexpressed GPR146 significantly increased secreted APOB100 levels”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both chow-fed male and female GPR146-deficient mice displayed significantly reduced TG and cholesterol secretion rates (Figure 2A and 2B, S2L and S2M) compared to wild-type littermates.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“plasma TC levels were significantly reduced by 20% in male and by 25% in female Gpr146−/− mice fed chow compared to Gpr146+/+ littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Livers from male Gpr146−/− mice showed decreased mRNA levels of Hmgcr encoding the rate-limiting enzyme for cholesterol biosynthesis, as well as decreased mRNA levels of Hmgcs1 and Pmvk”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“protein levels of the mature SREBP2, the master transcriptional regulator of cholesterol biosynthesis (Horton et al., 2002; Rong et al., 2017), were significantly decreased in liver of Gpr146−/− male mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HDL-C, LDL-C and very low density lipoprotein cholesterol (VLDL-C) were reduced by ~15%, ~35% and ~25%, respectively”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“hepatocyte-specific GPR146 depletion in Alb-Cre+ Gpr146fl/fl mice substantially reduced plasma TC levels by ~20% (male: 74.2 ± 6.1 mg/dl vs 61.2 ± 6.4 mg/dl; female: 61.8 ± 6.1 mg/dl vs 48.4 ± 3.2 mg/dl) compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“depletion of GPR146 in mice reduces circulating LDL-C levels substantially”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found the greatest reduction of APOB100 in fraction containing small size LDL particles”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the expression of heterodimeric ABC transporter ABCG5/G8, which mediates biliary cholesterol secretion at the apical membrane of hepatocytes (Graf et al., 2003; Yu et al., 2002), was not impaired in GPR146-deficient mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“liver contents of TG/TC in Gpr146−/− mice were similar to Gpr146+/+ control mice fed chow”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Gene sets enrichment analysis using KEGG gene sets revealed mitogen-activated protein kinase (MAPK) signaling as one of the significantly downregulated pathways in liver of Gpr146−/− mice upon feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“hepatic ERK1/2 activities are substantially increased upon feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While liver TC concentrations were similar between Gpr146+/+ mice and Gpr146−/− littermates upon chow feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we also measured mRNA levels of cholesterol biosynthetic genes in livers of refed female mice, and found downregulation of many genes including Hmgcr, Hmgcs1, Pmvk, Mvk and Mvd”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 is most highly expressed in white adipose tissue in both human and mouse (Figure 1D)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we over-expressed human GPR146 in HepG2 cells and found substantially increased levels of phosphor-ERK1/2 compared to GFP control upon serum stimulation”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the LDL-lowering effect upon GPR146 depletion does not require LDLR activity”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 deficiency reduced plasma TC levels by ~20% in mice fed chow and by ~30% in mice fed WD”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA levels of many cholesterol biosynthetic genes in liver were downregulated in the absence of GPR146”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates ERK/SREBP2 Axis in Mice upon Short Period of Fasting
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and ~60% and ~35% respective reductions in male and female Gpr146−/− Ldlr−/− mice fed WD compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“AAV-induced depletion of GPR146 also reduced mRNA levels of many cholesterol biosynthetic genes in liver compared to scramble control”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“plasma TC levels were significantly reduced in GPR146-deficient mice upon 6-hour fasting compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates ERK/SREBP2 Axis in Mice upon Short Period of Fasting
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA levels of many cholesterol biosynthetic genes in liver were downregulated in the absence of GPR146 in both male and female mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA levels of cholesterol biosynthetic genes, such as Srebp2, Hmgcr, Mvd and Ldlr, were downregulated in liver treated with PD0325901 compared to vehicle control”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasma TG levels were also substantially reduced by ~55% and ~25% in male and female GPR146-depleted mice compared to control littermates upon four weeks of WD feeding, respectively”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The fact that the cholesterol-lowering effect upon GPR146 depletion was accompanied by reduced hepatic LDLR expression”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Through both in vivo and in vitro studies, we discovered that ERK1/2 signaling is required for upregulation of SREBP2 pathway in hepatocytes upon feeding.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 mRNA expression level in liver was strongly reduced by 75% compared to scramble control”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Gene set enrichment analysis of liver transcriptome revealed that growth hormone receptor signaling cascade was significantly downregulated upon GPR146 depletion.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Upon WD feeding for four weeks, plasma TC levels were reduced by ~50% and ~30%, respectively, in male and female GPR146-depleted mice compared to control mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a single dose of PD0325901 treatment (10 mg/kg) significantly reduced plasma TC levels in 24-week old mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pERK1/2, precursor and mature SREBP2 protein levels were significantly reduced in liver of GPR146-deficient mice compared to control littermates upon 6-hour fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates ERK/SREBP2 Axis in Mice upon Short Period of Fasting
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“protein levels of pERK1/2, precursor and mature SREBP2 were substantially reduced in liver of GPR146-deficient mice compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“upon western diet feeding for 16 weeks, male and female Gpr146−/− Ldlr−/− mice exhibited ~60% and ~35% reductions of plasma TC levels, respectively, compared to Gpr146+/+ Ldlr−/− littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The Ldlr−/− mouse lipid profile more closely resembles that of dyslipidemic humans.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further analysis of cholesterol levels in atherogenic VLDL/LDL fraction of plasma showed ~35% reduction in both male and female Gpr146−/− Ldlr−/− mice fed chow”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the chow diet, plasma TC levels were reduced by ~30% in both male and female Gpr146−/− Ldlr−/− mice compared to Gpr146+/+Ldlr−/− littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The Ldlr−/− mouse lipid profile more closely resembles that of dyslipidemic humans.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while it had no additional effect in Gpr146−/− mice compared to vehicle control (vehicle vs PD: 53.1 ± 5.4 mg/dl vs 55.8 ± 1.9 mg/dl)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although evidence from both in vivo and in vitro studies unequivocally demonstrated that GPR146 is required for ERK1/2 activation in hepatocytes upon feeding, the detailed signaling cascade is still under investigation.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“plasma TC levels were reduced by ~34% and ~23%, respectively, in male and female mice treated with Gpr146-shRNA compared with scramble-shRNA at two weeks post-injection”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“plasma TG levels were reduced by ~37% and ~50%, respectively, in male and female Gpr146−/− Ldlr−/− mice fed chow compared to Gpr146+/+ Ldlr−/− littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Inhibition of ERK1/2 reduced mRNA levels of Srebp2, Hmgcr and Ldlr in both in vitro-cultured hepatocyte and liver upon feeding.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“cholesterol levels in VLDL/LDL fraction of plasma showed ~55% and ~32% reductions in male and female GPR146-depleted mice upon four weeks of WD feeding, respectively”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found significantly reduced expression of all three EGR genes in liver of GPR146-deficient mice upon feeding (data not shown).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mRNA levels of Srebp2 and its target genes Hmgcr and Ldlr in liver were significantly reduced in wild-type mice but not in Gpr146−/− mice after 6-hour refeeding upon MEK1/ERK1/2 inhibition”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Atherosclerotic lesion area evaluated by en face Oil Red O staining of the full-length aorta was drastically reduced by ~90% and ~70%, respectively, in male and female Gpr146−/− Ldlr−/− mice fed WD for 16 weeks compared to Gpr146+/+ Ldlr−/− littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Protects Against Atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PD0325901 treatment reduced plasma TC levels in a dose-dependent manner (vehicle vs PD 5mg/kg vs PD 10mg/kg: 86.3 ± 7.6 mg/dl vs 77.2 ± 4.7 mg/dl vs 68.4 ± 9.7 mg/dl)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we first confirmed that hepatic ERK1/2 activities decreased over time during fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates ERK/SREBP2 Axis in Mice upon Short Period of Fasting
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PD0325901 treatment exhibited a dose-dependent reduction of refed pERK1/2 levels in liver of 14-week old mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 deficiency led to diminished activities of ERK1/2 and SREBP2 only in a fasting-refeeding paradigm (6-hour refeeding after a 16-hour fast), not upon prolonged fasting (16-hour fasting)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates ERK/SREBP2 Axis in Mice upon Short Period of Fasting
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and by ~77% and ~50%, respectively, in male and female Gpr146−/− Ldlr−/− mice fed WD compared to control mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Atherosclerotic lesion area evaluated by en face Oil Red O staining of the full-length aorta was drastically reduced by ~90% and ~70%, respectively, in male and female Gpr146−/− Ldlr−/− mice fed WD for 16 weeks compared to Gpr146+/+ Ldlr−/− littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Protects Against Atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that the hepatic TG/TC homeostasis is well maintained despite reduced VLDL secretion rate”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data indicate that GPR146 plays a consistent role in regulation of circulating cholesterol levels in human and mouse”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and Triglycerides (TG) levels”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“thereby regulating hepatic very low-density lipoprotein (VLDL) secretion”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“depletion of GPR146 reduces plasma TC levels substantially upon different dietary lipid levels or different feeding conditions”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data show that GPR146 in hepatocyte plays a regulatory role in VLDL metabolism”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data suggest that GPR146 is likely to promote circulating cholesterol levels in humans”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
hedgedconditionaln = 2,116- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, differential intestinal absorption is unlikely to be the primary reason for the reduced plasma TC levels in GPR146-deficient mice.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which, in turn, protects against atherosclerosis”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Body composition analysis revealed similar fat mass for each group of mice fed chow”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reduced plasma LDL-C and TG levels in Gpr146−/− mice are very likely due to decreased hepatic VLDL secretion rate”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that GPR146 deficiency reduced plasma cholesterol levels more efficiently in the presence of high dietary cholesterol levels”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“through activation of the extracellular signal-regulated kinase (ERK) signaling pathway”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data taken together suggest that ERK activities are required for full activation of SREBP2 pathway in hepatocytes upon feeding.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data taken together suggests that GPR146 upon ligand binding stimulates ERK1/2 activities in liver upon feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“and was not detectable in Gpr146−/− mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that diminished plasma TC levels in the absence of GPR146 is independent of adiposity”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, it is possible that the GPR146/ERK axis modulates SREBP2 activity through both transcriptional regulation and posttranslational modification.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All these in vitro and in vivo data together suggest that ERK1/2 plays a role in cholesterol metabolism”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we provide several lines of evidence that the GPR146/ERK/SREBP2 axis regulates plasma cholesterol levels and depletion of GPR146 protects against hypercholesterolemia and atherosclerosis in LDLR-deficient mice.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that GPR146/ERK/SREBP2 axis starts operating upon feeding, further lasts for at least 6 hours postprandially, and eventually decreases to baseline after a prolonged fasting (16-hour fasting).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data suggest that the LDLR activity is not required for TC-lowering effect upon GPR146 depletion”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, antagonists targeting GPR146 are likely to be an efficient approach to tackle atherosclerotic cardiovascular disease in both the general population and HoFH patients.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146/ERK/SREBP2 axis is still in operation in LDLR-deficient mice upon feeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“there is no difference in body weight between Gpr146+/+ Ldlr−/− mice and Gpr146−/− Ldlr−/− littermate after feeding with WD for 16 weeks”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 regulates hepatic SREBP2 activities and plasma cholesterol levels through, at least in part, the ERK1/2 signaling cascade”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data suggest that acute depletion of GPR146 in liver of adult mice reduced plasma TC levels to a similar extent compared to germline knockout of GPR146”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Knockdown of Hepatic GPR146 by AAV-delivered shRNA Lowers Plasma Cholesterol Levels in Mice Lacking LDLR
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“strongly suggesting reduction of ERK1/2 activity as a key mechanism for decreased plasma TC levels in Gpr146−/− mice”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that GPR146/ERK/SREBP2 axis starts operating upon feeding, further lasts for at least 6 hours postprandially, and eventually decreases to baseline after a prolonged fasting (16-hour fasting).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that GPR146/ERK/SREBP2 axis starts operating upon feeding, further lasts for at least 6 hours postprandially, and eventually decreases to baseline after a prolonged fasting (16-hour fasting).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which suggest that there might be other GPR146 downstream pathways modulating plasma TC levels under this condition.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the downregulated cholesterol biosynthesis pathway upon GPR146 depletion might be a synergistic effect by reduced expression of SREBP2 and EGR genes.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, GPR146 deficiency confers protection against atherosclerosis to mice lacking LDLR.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Protects Against Atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study thus uncovers GPR146 as a new therapeutic target to treat hypercholesterolemia.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 26
- It may state two separate claims as one. 16
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ERK1/2 signaling has been previously shown to regulate SREBP2 activity in HepG2 cells via direct phosphorylation (Arito et al., 2008; Kotzka et al., 2004; Kotzka et al., 2000)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
What the sources say
- Partly supportedcites Arito et al., 2008 sourceExperimental — accuracy not yet measured
The Ser 455 results (page not available) link ERK activation to SREBP-2 phosphorylation and reduced sumoylation, while the HepG2 experiments show that inhibiting the ERK cascade increases SREBP-2 sumoylation. The phosphorylation experiments described in our copy were performed in COS-1 cells, however; they do not directly demonstrate ERK1/2 phosphorylation of SREBP-2 in HepG2 cells. (LLM, conf=0.84)
- Supportedcites Kotzka et al., 2004 source
The Results report that activating the Erk-MAPK pathway with MEK2D increased SREBP-2 trans-activity in HepG2 cells, while mutation of its phosphorylation sites greatly reduced or eliminated that response. The paper also identifies Ser-432 and Ser-455 as sites directly phosphorylated by Erk1/2. No page number is available in our copy. (LLM, conf=0.93)
- Partly supportedcites Kotzka et al., 2000 sourceExperimental — accuracy not yet measured
The Results report that MAP-kinase pathway activation increased SREBP-2 transcriptional activity in HepG2 cells, and that ERK1 or ERK2 directly phosphorylated recombinant SREBP-2 in vitro. The Abstract describes SREBP-2 as *possibly* a direct ERK1/2 substrate; it does not establish that direct phosphorylation mediates the activity change in HepG2 cells. Page numbers are not available in the supplied passages. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Abundant evidence demonstrates that hepatic SREBP2 activity and expression of its target genes such as HMGCR and LDLR fall while fasting and rise substantially upon refeeding”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
What the sources say
- Partly supportedcites Horton et al., 1998 sourceExperimental — accuracy not yet measured
The Results and Discussion report that nuclear SREBP-2 and LDL receptor mRNA decline during fasting and return to approximately basal levels after refeeding. But the Results say HMG-CoA reductase (HMGCR) mRNA changes little during fasting, so the claim that this target gene falls while fasting is not supported. The paper also distinguishes the return of SREBP-2 and cholesterol-related genes to basal levels from the above-basal overshoot seen for SREBP-1 and lipogenic genes. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Liang et al., 2002 source
- Partly supportedcites Matsuda et al., 2001 sourceExperimental — accuracy not yet measured
The Results (page not supplied) report that fasting reduced hepatic SREBP-2 mRNA and SREBP target-gene mRNAs in wild-type mice, and that refeeding raised several target-gene mRNAs above normal, notably HMG-CoA reductase. The passage does not establish that SREBP-2 activity rose substantially on refeeding or that LDL receptor expression had a similarly substantial rise. (LLM, conf=0.82)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“There are over 300 loci uncovered to be associated with plasma lipid levels in humans (Klarin et al., 2018; Liu et al., 2017; Teslovich et al., 2010; Willer et al., 2013).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
What the sources say
- Supportedcites Klarin et al., 2018 source
The Results section ('Lipid Genetic Association and Conditional Analyses') reports 118 novel and 268 previously identified loci associated with plasma lipid levels—a total of 386. The Discussion describes this as nearly 400 known independent genetic lipid loci, supporting the claim that there are over 300. (LLM, conf=0.94)
- Partly supportedcites Liu et al., 2017 sourceExperimental — accuracy not yet measured
The paper reports loci associated with plasma lipid levels in humans, but its Abstract gives 250 loci—75 novel and 175 previously implicated—not over 300. It therefore supports the existence of lipid-associated loci but does not establish the cited sentence’s numerical threshold. (LLM, conf=0.87)
- Partly supportedcites Teslovich et al., 2010 sourceExperimental — accuracy not yet measured
The “Genome-Wide Association Mapping in >100,000 Individuals” section reports 95 lipid-associated loci, including 59 reported for the first time. This supports the existence of loci associated with human lipid levels, but this source does not establish the citing sentence’s total of over 300 loci. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Substantial evidence supports the conclusion that hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding, indicating the existence of feeding-responsive signaling pathways upregulating hepatic cholesterol synthesis in the presence of dietary nutrition (Horton et al., 1998; Liang et al., 2002; Matsuda et al., 2001; Slakey et al., 1972).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Partly supportedcites Horton et al., 1998 sourceExperimental — accuracy not yet measured
The Results and Discussion report that hepatic nuclear SREBP-2 falls during fasting and recovers upon refeeding. But they specify that it returns only to the nonfasted level; the Abstract says cholesterol synthesis likewise returns only to its prefasted level. The paper therefore supports a fasting decline and refeeding recovery, but not an increase greatly beyond baseline. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Liang et al., 2002 source
- Partly supportedcites Matsuda et al., 2001 sourceExperimental — accuracy not yet measured
The Results (page unavailable) report that fasting reduced hepatic SREBP-2 mRNA and cholesterol-synthesis target-gene mRNAs in mice; refeeding raised several target-gene mRNAs above their nonfasted levels. These findings support a feeding-responsive cholesterol-synthesis pathway, but the cited passage does not establish that SREBP-2 activity and the measured rate of cholesterol biosynthesis both fell during fasting and rose greatly upon refeeding. (LLM, conf=0.84)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“SREBP2 may maintain promoters of target genes in a receptive state for binding of those transcription factors (Gokey et al., 2011; Liang et al., 2002).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Supportedcites Gokey et al., 2011 source
The passage labeled Abstract describes a proposed model in which SREBP-2 maintains target promoters in a receptive state for binding by additional insulin-dependent transcription factors. The “Egr1 Regulates Cholesterol Synthesis” section repeats that permissive-factor model. The claim’s “may” preserves its tentative status; page numbers are not supplied in our copy. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Liang et al., 2002 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Moreover, there is longstanding evidence showing that, besides SREBP2, additional feeding-responsive transcription factors are likely to promote expression of cholesterol biosynthetic genes.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Supportedcites Gokey et al., 2011 source
The Discussion says there is substantial evidence that factors other than SREBPs regulate lipid biosynthetic genes in response to hormonal signals. The “Egr1 Regulates Cholesterol Synthesis” section describes a model in which other insulin-responsive transcription factors activate cholesterol biosynthetic promoters and reports a reduced feeding response for Sqle in Egr1-null mice. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites Liang et al., 2002 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In hepatocytes, many hormones and growth factors such as epidermal growth factors (EGF) and fibroblast growth factors (FGF) are able to stimulate ERK1/2 signaling cascade (Fremin et al., 2007; Guegan et al., 2012).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Not checked — no full text of the sourcecites Fremin et al., 2007 source
- Partly supportedcites Guegan et al., 2012 sourceExperimental — accuracy not yet measured
The Introduction and section 2 describe growth-factor activation of MEK–ERK signaling in hepatocytes and specifically discuss EGF, HGF, IGF-1, and growth hormone. They do not identify FGF as an ERK1/2 stimulus in hepatocytes, so that example is not supported by our copy. Page numbers are unavailable. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Previous studies in HepG2 cells showed that MEK1/ERK cascade directly phosphorylates SREBP2 at Ser-432 and Ser-455, which inhibits its sumoylation and subsequently promotes its transcription activity (Arito et al., 2008; Kotzka et al., 2004; Kotzka et al., 2000).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Partly supportedcites Arito et al., 2008 sourceExperimental — accuracy not yet measured
In “Ser 455 of SREBP-2 Is Critical for SUMO-1 Conjugation” (page unavailable), the paper identifies Ser-432 and Ser-455 as phosphorylation sites, but reports that mutating Ser-432 had no effect on sumoylation; the inhibitory link is specific to Ser-455. The paper connects ERK-pathway activity, reduced sumoylation, and increased transcriptional activity, but its site-specific experiments were chiefly in COS-1 cells and do not directly demonstrate MEK1/ERK phosphorylation at both sites in HepG2 cells. (LLM, conf=0.88)
- Partly supportedcites Kotzka et al., 2004 sourceExperimental — accuracy not yet measured
The Results identify Ser-432 and Ser-455 as Erk2 phosphorylation sites and show that activating the Erk pathway with MEK2D increases SREBP-2 transcriptional activity in HepG2 cells. Our copy does not establish that phosphorylation inhibits sumoylation, and the HepG2 experiment uses MEK2D rather than MEK1. (LLM, conf=0.89)
- Partly supportedcites Kotzka et al., 2000 sourceExperimental — accuracy not yet measured
The Results report that ERK1 and ERK2 phosphorylated SREBP-2 on serine residues in vitro, and that activating the MAP-kinase cascade increased SREBP-2 transcriptional activity in HepG2 cells. The paper does not identify Ser-432 or Ser-455, test sumoylation, or establish that phosphorylation at those sites causes the increased activity. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Downregulation of cholesterol biosynthetic genes in the absence of GPR146 was observed under fasting-refeeding conditions, but not in mice after a prolonged 16-hour fasting”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice upon PD0325901 administration exhibited significantly reduced refed phosphor-ERK1/2 (pERK1/2) levels in liver, but not reduced levels of other MAPK families, such as phosphor-JNK and phosphor-P38”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Refed SREBP2 Signaling Pathway and Plasma TC Levels Through ERK1/2
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“there was a trend towards reduction in male Gpr146−/− mice and a significant decrease in female Gpr146−/− mice upon western diet feeding for two months, compared to control littermates”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is worth noting that there remains a significant reduction of plasma TC levels in the absence of GPR146 upon a prolonged 16-hour fasting despite no changes of ERK1/2 and SREBP2 activities”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Metabolic profiling of mice fed chow showed no difference in either food/water intake or locomotor activity (Figure S2A–S2C) between Gpr146−/− and Gpr146+/+ littermates.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Deficiency Reduces Hepatic SREBP2 Activity and VLDL Secretion Rate
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mating between Gpr146+/− mice produced offspring in the expected Mendelian 1:2:1 ratio.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“it is well established that many GPCRs activate ERK1/2 signaling upon ligand binding (van Biesen et al., 1996)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Signaling Promotes ERK1/2 Activities in Hepatocytes Upon Feeding
What the sources say
- Not checked — no full text of the sourcecites van Biesen et al., 1996 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Gpr146−/− mice were viable, fertile and normal in appearance.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > GPR146 Regulates Plasma Cholesterol Levels in Both Human and Mouse
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“elevated plasma LDL-C and TG levels are major risk factors (Defesche et al., 2017; Do et al., 2013; Hegele, 2009; Hokanson and Austin, 1996; Rader, 2016)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“over 95% of HoFH patients have loss-of-function mutations in both LDLR alleles (Defesche et al., 2017)”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites Defesche et al., 2017 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“thereby increasing SREBP2 activities and VLDL secretion rate”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Melting curve analysis was carried out to confirm the RT-PCR products.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we provide several lines of evidence that the GPR146/ERK/SREBP2 axis regulates plasma cholesterol levels and depletion of GPR146 protects against hypercholesterolemia and atherosclerosis in LDLR-deficient mice.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample size.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“RNA quality was verified using the Agilent Bioanalyzer and the 6000 nano kit.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We further put forward a signaling pathway in which GPR146 promotes ERK1/2 signaling cascade in hepatocytes upon feeding, which in turn increases SREBP2 activities and VLDL secretion rate”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Defects in this regulation lead to dramatically elevated plasma LDL-C levels in HoFH patients due to increased hepatic cholesterol synthesis as well as decreased LDL-C clearance (Brown and Goldstein, 1975, 1986; Goldstein and Brown, 1973).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
What the sources say
- Not matchedcites Brown and Goldstein, 1975, 1986
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked yetcites Goldstein and Brown, 1973 source
Checked before — its earlier verdict is held back until a new check runs.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Both male and female 6- to 36-week-old littermate mice were used in this study to match age and sex.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 upon ligand binding might directly activate ERK1/2 through activated Gα and Gβγ subunits and downstream signaling cascade; or GPR146 signaling might cross-talk with other growth factor/hormone signaling pathways to modulate ERK1/2 activities.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: GPR146 has a natural ligand.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GPR146 upon ligand binding might directly activate ERK1/2 through activated Gα and Gβγ subunits and downstream signaling cascade; or GPR146 signaling might cross-talk with other growth factor/hormone signaling pathways to modulate ERK1/2 activities.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
- Rests on an assumption: GPR146 has a natural ligand.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results show that depletion of GPR146 reduces circulating cholesterol and TG levels substantially and confers great protection to LDLR-deficient mice against atherosclerosis.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is well documented that many GPCRs upon ligand binding activate ERK signaling and further regulate cell growth, division and differentiation (van Biesen et al., 1996).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Not checked — no full text of the sourcecites van Biesen et al., 1996 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Feedback suppression of SREBP2 pathway by LDLR plays a pivotal role in maintaining the balance of cholesterol levels between liver and blood (Brown and Goldstein, 1986).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > RESULTS > Cholesterol-lowering Effect upon GPR146 Depletion Does Not Require LDLR Activity
What the sources say
- Not checked — no full text of the sourcecites Brown and Goldstein, 1986 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All image capture and quantitation were done in a blinded fashion.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The early growth response gene family (EGR1, EGR2 and EGR3), which are ERK1/2 target genes, have previously been indicated as additional transcription factors to upregulate cholesterol biosynthetic gene expression upon feeding (Gokey et al., 2011).”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > DISCUSSION > The Role of GPR146 in Regulation of Hepatic ERK1/2 and SREBP2 Pathways
What the sources say
- Not checked yetcites Gokey et al., 2011 source
Checked before — its earlier verdict is held back until a new check runs.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not checked yet
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To reduce the frequency of homologous recombination of long terminal repeat (LTRs), E. coli stbl3 strain cultured in LB broth was used to clone all of the lentiviral vectors.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal care and experimental procedures used in this study were approved by the Institutional Animal Care and Use Committee at Harvard University and Beth Israel Deaconess Medical Center.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Genome-edited F1 Gpr146−/− and Gpr146+/fl mice were bred with C57BL/6 mice for two rounds to dilute the off-target effects.”
§ GPR146 Deficiency Protects Against Hypercholesterolemia and Atherosclerosis > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The molecular functions of the over 300 lipid-associated loci are not fully characterized.
“However, their molecular functions are not fully characterized.”
The paper relies on this without support.
The in vivo physiological function of ERK1/2 signaling in regulation of hepatic cholesterol metabolism is unknown.
“However, the in vivo physiological function of ERK1/2 signaling in regulation of hepatic cholesterol metabolism is unknown.”
The paper relies on this without support.
The Ldlr−/− mouse lipid profile more closely resembles that of dyslipidemic humans.
“the lipid profile of which more closely resembles that of dyslipidemic humans (the predominant lipoprotein is the APOB100-containing LDL)”
The paper relies on this without support.
GPR146 has a natural ligand.
“This also suggests that the amount of natural ligand for GPR146 might be upregulated upon feeding, or GPR146 might cross-talk with other signaling pathways that are activated upon feeding to regulate hepatic ERK1/2 activities.”
Citations
Cites
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15593 · Cited by 4,794
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092
Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., & Jaenisch, R. (2013) · Cell · doi:10.1016/j.cell.2013.04.025 · Cited by 3,495
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487
Willer (2013) · doi:10.1038/ng.2797 · Cited by 2,983
Self-citationHokanson, J. E., & Austin, M. A. (1996) · Journal of Cardiovascular Risk · doi:10.1097/00043798-199604000-00014 · Cited by 1,706
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GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential
Ma, X., Liu, Z., Ilyas, I., Little, P. J., Kamato, D., Sahebka, A., Chen, Z., Luo, S., Zheng, X., Weng, J., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.59965 · Cited by 299
Self-citationCui, D., Yu, X., Guan, Q., Shen, Y., Liao, J., Liu, Y., & Su, Z. (2025) · Molecular Biomedicine · doi:10.1186/s43556-025-00321-3 · Cited by 126
Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans
Wang, X., Wang, H., Xu, B., Huang, D., Nie, C., Pu, L., Zajac, G. J. M., Yan, H., Zhao, J., Shi, F., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.020 · Cited by 115
A gut-derived hormone regulates cholesterol metabolism
Hu, X., Chen, F., Jia, L., 隆爱军, Peng, Y. C., Li, X., Huang, J., Wei, X., Fang, X., Gao, Z., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.024 · Cited by 109
VLDL Biogenesis and Secretion: It Takes a Village
Zwol, W. H.-V., van de Sluis, B., Ginsberg, H. N., & Kuivenhoven, J. A. (2024) · Circulation Research · doi:10.1161/circresaha.123.323284 · Cited by 90
Self-citation
Metadata
- Authors
- Yu, H., Rimbert, A., Palmer, A. E., Toyohara, T., Xia, Y., Xia, F., Ferreira, L. M. R., Chen, Z., Chen, T., Loaiza, N., Horwitz, N. B., Kacergis, M. C., Zhao, L., Soukas, A. A., Kuivenhoven, J. A., Kathiresan, S., & Cowan, C. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- University Medical Center Groningen (NL)
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Corresponding author
- Yu, Haojie
- Cowan, Chad A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 179
- Issue
- 6
- Pages
- 1276-1288.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6889877
- OpenAlex
- W2990248610
- Cited by
- 113
- References
- 45
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 30 · 2023: 13 · 2022: 17 · 2021: 10 · 2020: 7 · 2019: 2
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Institutes of Health (NHLBI/R33HL120781, NIDDK/R01DK097768)
- Nutrition Obesity Research Center of Harvard (P30DK040561)
- Netherlands CardioVascular Research Initiative
- Established Investigator of the Netherlands Heart Foundation (CVON2017-2020, 2015T068)
- Institut de France-Fondation Lefoulon-Delalande Postdoctoral Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- GPR146, orphan G protein-coupled receptor, SREBP2, ERK signaling, hepatic VLDL secretion, LDL cholesterol, triglycerides, hypercholesterolemia, atherosclerosis, LDL receptor deficiency, cholesterol metabolism, plasma lipids
- MeSH terms
- Dependovirus, Animals, Base Sequence, Cholesterol, Fasting, Female, Humans, Hypercholesterolemia, Lipoproteins, VLDL, Liver, Mice, Inbred C57BL, Receptors, LDL, Triglycerides, Signal Transduction, Up-Regulation, Hepatocytes, RNA, Small Interfering, Receptors, G-Protein-Coupled, Extracellular Signal-Regulated MAP Kinases, Atherosclerosis, Mice, Sterol Regulatory Element Binding Protein 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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