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Cited by 115Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

The DOI matches its Crossref record; 44 of the 45 references it cites were found in a registry or an index; 23 of the 45 sources its claims cite were checked for support.

GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

Open access
Yu, Haojie, Rimbert, Antoine, Palmer, Alice E., Toyohara, Takafumi, Xia, Yulei, Xia, Fang, Ferreira, Leonardo M.R., Chen, Zhifen, Chen, Tao, Loaiza, Natalia, Horwitz, Nathaniel Brooks, Kacergis, Michael C., Zhao, Liping, Soukas, Alexander A., Kuivenhoven, Jan Albert, Kathiresan, Sekar, Cowan, Chad A.·2019·Cell
DOI 10.1016/j.cell.2019.10.034PMC PMC6889877
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Abstract

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

AI snapshot

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.”

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2019.10.034

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

23 of 45 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    GPR146 is a susceptible gene associated with plasma total cholesterol (TC), LDL-C and HDL-C levels.

    “GPR146, a susceptible gene associated with plasma total cholesterol (TC), LDL-C and high density lipoprotein cholesterol (HDL-C) levels”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Klarin et al., 2018 source

      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)

      Experimental — accuracy not yet measured
    • cites Liu et al., 2017 source

      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)

      Experimental — accuracy not yet measured
    • cites Teslovich et al., 2010 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    The alternative allele of rs1997243-G, located 11-kb upstream of GPR146, is associated with increased plasma TC, HDL-C and LDL-C levels in humans.

    “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)”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Klarin et al., 2018 source

      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)

      Experimental — accuracy not yet measured
    • cites Liu et al., 2017 source

      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)

      Experimental — accuracy not yet measured
    • cites Willer et al., 2013 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    HoFH patients have markedly diminished response to statins and PCSK9 inhibitors because their lipid-lowering effects require upregulation of LDLR activity.

    “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).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Cuchel et al., 2014 source

      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)

      Experimental — accuracy not yet measured
    • cites Defesche et al., 2017 source
  • Premisecitation

    Human genetic studies have unequivocally established GPR146 as a susceptible gene regulating plasma cholesterol levels.

    “Human genetic studies have unequivocally established GPR146 as a susceptible gene regulating plasma cholesterol levels.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Klarin et al., 2018 source

      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)

      Experimental — accuracy not yet measured
    • cites Liu et al., 2017 source

      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)

      Experimental — accuracy not yet measured
    • cites Willer et al., 2013 source

      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)

      Experimental — accuracy not yet measured
  • Findingown data

    Depletion of GPR146 in Huh7 cells has no effect on uptake of LDL particles.

    “depletion of GPR146 in Huh7 cells has no effect on uptake of LDL particles”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 26
  • It may state two separate claims as one. 16

  • Probably not a substantial claim.

    Premisecitation

    ERK1/2 signaling has been previously shown to regulate SREBP2 activity in HepG2 cells via direct phosphorylation.

    “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)”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Arito et al., 2008 source

      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)

      Experimental — accuracy not yet measured
    • cites Kotzka et al., 2004 source
    • cites Kotzka et al., 2000 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    There are over 300 loci uncovered to be associated with plasma lipid levels in humans.

    “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).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Klarin et al., 2018 source
    • cites Liu et al., 2017 source

      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)

      Experimental — accuracy not yet measured
    • cites Teslovich et al., 2010 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Hepatic SREBP2 activity and cholesterol biosynthesis rate fall while fasting and rise greatly upon refeeding.

    “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).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Horton et al., 1998 source

      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)

      Experimental — accuracy not yet measured
    • cites Liang et al., 2002 source
    • cites Matsuda et al., 2001 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    SREBP2 may maintain promoters of target genes in a receptive state for binding of those transcription factors.

    “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).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Gokey et al., 2011 source
    • cites Liang et al., 2002 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In hepatocytes, many hormones and growth factors such as EGF and FGF stimulate ERK1/2 signaling.

    “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).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Fremin et al., 2007 source
    • cites Guegan et al., 2012 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    The MEK1/ERK cascade directly phosphorylates SREBP2 at Ser-432 and Ser-455, inhibiting its sumoylation and promoting its transcription activity.

    “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).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Arito et al., 2008 source

      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)

      Experimental — accuracy not yet measured
    • cites Kotzka et al., 2004 source

      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)

      Experimental — accuracy not yet measured
    • cites Kotzka et al., 2000 source

      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)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    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.

    “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”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    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.

    “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”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    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.

    “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”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Plasma total cholesterol levels are significantly reduced in the absence of GPR146 after a prolonged 16-hour fast, despite no changes in ERK1/2 and SREBP2 activities.

    “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”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Metabolic profiling showed no difference in food/water intake or locomotor activity between Gpr146−/− and Gpr146+/+ littermates.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Hepatic SREBP2 activity and expression of its target genes such as HMGCR and LDLR fall while fasting and rise substantially upon refeeding.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Horton et al., 1998 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites Liang et al., 2002 source
    • cites Matsuda et al., 2001 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Mating between Gpr146+/− mice produced offspring in the expected Mendelian 1:2:1 ratio.

    “Mating between Gpr146+/− mice produced offspring in the expected Mendelian 1:2:1 ratio.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Many GPCRs activate ERK1/2 signaling upon ligand binding.

    “it is well established that many GPCRs activate ERK1/2 signaling upon ligand binding (van Biesen et al., 1996)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites van Biesen et al., 1996 source

  • It may state two separate claims as one.

    Study design and conductown data

    Gpr146−/− mice were viable, fertile and normal in appearance.

    “Gpr146−/− mice were viable, fertile and normal in appearance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    Elevated plasma LDL-C and TG levels are major risk factors for atherosclerotic cardiovascular disease.

    “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)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Defesche et al., 2017 source
    • cites Do et al., 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Hegele, 2009 source

  • Probably not a substantial claim.

    Premisecitation

    Over 95% of HoFH patients have loss-of-function mutations in both LDLR alleles.

    “over 95% of HoFH patients have loss-of-function mutations in both LDLR alleles (Defesche et al., 2017)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Defesche et al., 2017 source

  • It may state two separate claims as one.

    Interpretationreasoning

    GPR146 increases SREBP2 activities and VLDL secretion rate.

    “thereby increasing SREBP2 activities and VLDL secretion rate”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Melting curve analysis was carried out to confirm the RT-PCR products.

    “Melting curve analysis was carried out to confirm the RT-PCR products.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Depletion of GPR146 protects against hypercholesterolemia and atherosclerosis in LDLR-deficient mice.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No statistical methods were used to predetermine sample size.

    “No statistical methods were used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    RNA quality was verified using the Agilent Bioanalyzer and the 6000 nano kit.

    “RNA quality was verified using the Agilent Bioanalyzer and the 6000 nano kit.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    GPR146 promotes ERK1/2 signaling cascade in hepatocytes upon feeding, which in turn increases SREBP2 activities and VLDL secretion rate.

    “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”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brown and Goldstein, 1975, 1986

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Goldstein and Brown, 1973 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Both male and female 6- to 36-week-old littermate mice were used to match age and sex.

    “Both male and female 6- to 36-week-old littermate mice were used in this study to match age and sex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Besides SREBP2, additional feeding-responsive transcription factors likely promote expression of cholesterol biosynthetic genes.

    “Moreover, there is longstanding evidence showing that, besides SREBP2, additional feeding-responsive transcription factors are likely to promote expression of cholesterol biosynthetic genes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Gokey et al., 2011 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites Liang et al., 2002 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    GPR146 signaling might cross-talk with other growth factor/hormone signaling pathways to modulate ERK1/2 activities.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GPR146 has a natural ligand.

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    GPR146 upon ligand binding might directly activate ERK1/2 through activated Gα and Gβγ subunits and downstream signaling cascade.

    “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.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GPR146 has a natural ligand.

  • It may state two separate claims as one.

    Interpretationown data

    Depletion of GPR146 reduces circulating cholesterol and TG levels substantially and confers great protection to LDLR-deficient mice against atherosclerosis.

    “Our results show that depletion of GPR146 reduces circulating cholesterol and TG levels substantially and confers great protection to LDLR-deficient mice against atherosclerosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Many GPCRs upon ligand binding activate ERK signaling and regulate cell growth, division and differentiation.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites van Biesen et al., 1996 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Feedback suppression of SREBP2 pathway by LDLR plays a pivotal role in maintaining the balance of cholesterol levels between liver and blood.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brown and Goldstein, 1986 source

  • Probably not a substantial claim.

    Study design and conductnone given

    All image capture and quantitation were done in a blinded fashion.

    “All image capture and quantitation were done in a blinded fashion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    The early growth response gene family (EGR1, EGR2, EGR3) are ERK1/2 target genes and have been indicated as additional transcription factors that upregulate cholesterol biosynthetic gene expression upon feeding.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gokey et al., 2011 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    E. coli stbl3 strain was used to clone lentiviral vectors to reduce the frequency of homologous recombination of LTRs.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Genome-edited F1 Gpr146−/− and Gpr146+/fl mice were bred with C57BL/6 mice for two rounds to dilute off-target effects.

    “Genome-edited F1 Gpr146−/− and Gpr146+/fl mice were bred with C57BL/6 mice for two rounds to dilute the off-target effects.”
    Quote in the paperNot a substantial claim
36 of 36

  • 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.”
4 of 4

Citations

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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)
DOI
10.1016/j.cell.2019.10.034
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
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).

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Cited sources are checked with a language model’s help (gpt-6-sol).

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