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Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP
Open accessAbstract
Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.
Overview
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Written from the paper’s full text.
TL;DR
RNF145 is an LXR-induced ER membrane E3 ubiquitin ligase that ubiquitinates SCAP at lysines K454 and K466, inhibiting SCAP transport/SREBP-2 processing and cholesterol biosynthesis. Gain- and loss-of-function mouse studies show RNF145 lowers serum cholesterol and cholesterologenic gene expression, while RNF145 deficiency raises them.
Key findings
- Rnf145 is an LXR target gene: GW3965 increased Rnf145 expression two-fold in WT primary hepatocytes, but not in LXR DKO hepatocytes; hepatic Rnf145 was induced by GW3965 in mice and cynomolgus monkeys and by Western diet in WT but not Lxrαβ–/– mice. ChIP-seq showed LXRα/LXRβ binding and H3K27 acetylation at the Rnf145 locus.
- RNF145 overexpression lowered serum cholesterol in chow-fed C57BL/6 and Ldlr–/– mice, reduced HDL and LDL cholesterol fractions, inhibited hepatic cholesterologenic genes, and reduced mature nuclear SREBP-2 without changing membrane-bound precursor. These effects required intact Scap and RNF145 E3 activity; the RING mutant C537A had no effect on serum cholesterol or cholesterologenic gene suppression.
- RNF145 ubiquitinated SCAP on K454 and K466; K454R/K466R SCAP showed reduced ubiquitination, and RNF145 inhibited SREBP-2 processing in SCAP-knockout HEK293 cells reconstituted with WT SCAP but not with the lysine-mutant SCAP. SCAP protein abundance and turnover were not affected by RNF145.
- Acute Rnf145 knockdown suppressed endogenous hepatic Rnf145 mRNA by about 40%, modestly increased liver cholesterol, and elevated cholesterologenic genes without changing serum cholesterol or triglycerides. Rnf145–/– mice had increased serum cholesterol in LDL and HDL fractions and coordinated upregulation of the cholesterol biosynthetic pathway, with no change in liver cholesterol, liver triglycerides, or blood glucose; they showed slightly reduced body weight.
Methods
- In vivo mouse studies used adenoviral overexpression of GFP, RNF145, RING-mutant RNF145 (C537A), GP78, or TRC8; adenoviral shRNA against Rnf145; and CRISPR/Cas9-generated Rnf145–/– mice. Models included chow-fed C57BL/6, Ldlr–/–, liver-specific Scap–/–, LXR DKO, and WT littermates, with sample sizes such as N = 8 per group for adenoviral experiments and N = 16 WT / 14 Rnf145–/– for some knockout measurements.
- Cell and biochemical assays used HEK293T, CHO, and SCAP-knockout HEK293 cells; transient transfections; sterol depletion with lipoprotein-deficient serum plus simvastatin; MG132 treatment; immunoprecipitation; Western blotting; immunofluorescence; nuclear/membrane fractionation; real-time PCR; FPLC lipoprotein fractionation; microarray profiling; and ChIP-seq in immortalized bone marrow-derived macrophages.
- Statistical analysis used paired or non-paired Student’s t-test with significance at p < 0.05; * denotes p < 0.05 and denotes p < 0.01. Results are mean ± SEM unless otherwise specified, and experiments were performed at least twice.
Limitations
- The paper states that the basis for the differential response of SREBP-1 versus SREBP-2 target genes is unknown, that the identities of key endogenous LXR activators in liver remain to be fully determined, and that long-term studies under varied dietary conditions and tissue-specific loss-of-function models are needed.
- The paper notes that acute knockdown and chronic knockout of RNF145 had only partially overlapping effects, possibly due to compensatory mechanisms, and that SCAP–RNF145 interaction was not detected by co-immunoprecipitation, though this was not unexpected for transient E3–substrate interactions.
- The methods state that investigators were blinded to group allocation for some but not all studies; the paper also notes that another group did not observe metabolic consequences of acute RNF145 knockdown in vitro, whereas the Rnf145–/– mice revealed phenotypes not predicted by in vitro models.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
2 of 47 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Findingown data
RNF145 inhibited expression of cholesterologenic genes.
“In line with these effects on lipid levels, whereas RNF145 inhibited the expression of cholesterologenic genes, GP78 and TRC8 elevated expression of the genes involved in both cholesterol and triglyceride production (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Turnover of SCAP protein was not affected by exogenous expression of RNF145.
“We further confirmed using cycloheximide to block protein synthesis that the turnover of SCAP protein was not affected by exogenous expression of RNF145 (Figure 6—figure supplement 1B).”
Quote in the paperSubstantial claim - Findingown data
Rnf145 overexpression reduced levels of the mature, nuclear form of SREBP-2.
“We found that Rnf145 overexpression reduced the levels of the mature, nuclear form of SREBP-2, without affecting the membrane-bound precursor form (Figure 3I).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in liver cholesterol content between Gfp- and Rnf145-transduced Ldlr-/- groups.
“There was no difference in liver cholesterol content between Gfp- and Rnf145-transduced groups (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
Hepatic expression of genes involved in cholesterol biosynthesis was not suppressed by expression of RING-mutant Rnf145.
“Furthermore, the hepatic expression of genes involved in cholesterol biosynthesis was not suppressed by the expression of RING-mutant Rnf145 (Figure 5B).”
Quote in the paperSubstantial claim
- Findingown data
There was no change in liver triglyceride content with Rnf145 expression in liver-specific Scap-/- mice.
“There was also no change in liver cholesterol or triglyceride content with Rnf145 expression in liver-specific Scap–/– mice (Figure 3G and Figure 3—figure supplement 1E).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in cholesterol content of the liver between Gfp and Rnf145 groups.
“There was no difference in serum triglyceride levels or in cholesterol content of the liver between groups (Figure 3—figure supplement 1A and B).”
Quote in the paperNot a substantial claim - Findingown data
Serum cholesterol levels in Rnf145-/- mice were increased in both LDL and HDL fractions compared to WT littermates.
“Interestingly, serum cholesterol levels in Rnf145–/– mice were increased in both the LDL and HDL fractions compared to their WT littermates (Figure 4B and C).”
Quote in the paperSubstantial claim - Findingown data
Regulation of Rnf145 expression by LXR remained intact even with cycloheximide treatment.
“The regulation of Rnf145 expression by LXR remained intact even with cycloheximide treatment, suggesting that it was a direct transcriptional effect (Figure 1—figure supplement 1).”
Quote in the paperSubstantial claim - Findingown data
Expression of cholesterologenic genes was also suppressed by Rnf145 in Ldlr-/- mice.
“The expression of cholesterologenic genes was also suppressed by Rnf145 in Ldlr–/– mice (Figure 3—figure supplement 1C), suggesting that LDLR-mediated lipoprotein clearance was not required for these effects of RNF145 on hepatic gene expression.”
Quote in the paperSubstantial claim - Findingown data
ChIP-seq analysis revealed H3K27 acetylation in response to LXR activation in the same region.
“ChIP-seq analysis also revealed H3K27 acetylation in response to LXR activation in the same region.”
Quote in the paperNot a substantial claim - Findingown data
Cholesterol content in liver of mice expressing Rnf145-targeting shRNA was modestly increased.
“However, the cholesterol content in the liver of mice expressing Rnf145-targeting shRNA was modestly increased.”
Quote in the paperSubstantial claim - Findingown data
There was no difference in serum triglyceride levels between Gfp and Rnf145 groups.
“There was no difference in serum triglyceride levels or in cholesterol content of the liver between groups (Figure 3—figure supplement 1A and B).”
Quote in the paperNot a substantial claim - Findingown data
Fractionation of serum lipoproteins demonstrated reduced cholesterol in both HDL and LDL fractions in mice transduced with Rnf145.
“Fractionation of serum lipoproteins demonstrated reduced cholesterol in both the HDL and LDL fractions in mice transduced with Rnf145 (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
Genes involved in other biological processes, including cholesterol efflux, were largely unchanged in response to reduced Rnf145 expression.
“Furthermore, the expression of a number of cholesterologenic genes was elevated in response to reduced Rnf145 expression, while genes involved in other biological processes, including cholesterol efflux were largely unchanged (Figure 7B).”
Quote in the paperNot a substantial claim - Findingown data
Expression of a number of SREBP-2 target genes involved in sterol synthesis pathway was increased in genetic absence of Rnf145.
“Expression of a number of SREBP-2 target genes involved in the sterol synthesis pathway was increased in the genetic absence of Rnf145.”
Quote in the paperSubstantial claim - Findingown data
Rnf145 expression led to decreased serum cholesterol levels compared to Gfp expression in chow-fed C57BL/6 mice.
“Compared to Gfp expression, Rnf145 expression led to decreased serum cholesterol levels (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Expression of a number of cholesterologenic genes was elevated in response to reduced Rnf145 expression.
“Furthermore, the expression of a number of cholesterologenic genes was elevated in response to reduced Rnf145 expression, while genes involved in other biological processes, including cholesterol efflux were largely unchanged (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
Ubiquitination of mutant SCAP (K454R, K466R) was reduced compared to WT SCAP when transfected with RNF145.
“When we transfected the mutant SCAP into CHO cells together with RNF145, we found that the ubiquitination of the mutant SCAP was reduced compared to WT SCAP (Figure 6C), suggesting that RNF145 was targeting these lysine residues.”
Quote in the paperSubstantial claim - Findingown data
Expression of genes involved in other biological processes, including fatty acid biosynthesis, cholesterol efflux and gluconeogenesis, was not altered on Day 6.
“By contrast, the expression of genes involved in other biological processes, including fatty acid biosynthesis, cholesterol efflux and gluconeogenesis, was not altered on Day 6.”
Quote in the paperSubstantial claim - Findingown data
Rnf145 expression in primary hepatocytes from WT mice was increased two fold with GW3965 treatment.
“Rnf145 expression in primary hepatocytes from WT mice was increased two fold with GW3965 treatment (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
ChIP-seq analysis showed binding of both LXRα and LXRβ to the proximal regulatory region of the Rnf145 gene.
“This conclusion was corroborated by ChIP-seq analysis showing the binding of both LXRα and LXRβ to the proximal regulatory region of the Rnf145 gene (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
Sterol-regulated processing of SREBP-2 in cells receiving mutant RNF145, GP78, or TRC8, was comparable to controls.
“In contrast, the sterol-regulated processing of SREBP-2 in cells receiving mutant RNF145, GP78, or TRC8, was comparable to controls (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
Two lysine residues (K454 and K466) are positioned in proximity to residues important for COPII binding within the same cytoplasmic loop of SCAP.
“We noticed that there were two lysine residues (K454 and K466) positioned in proximity to the residues important for COPII binding within the same cytoplasmic loop (Figure 6—figure supplement 1D).”
Quote in the paperSubstantial claim - Findingown data
There was no change in serum triglyceride levels in mice transduced with any of the ligases.
“There was no change in serum or liver triglyceride levels in mice transduced with any of the ligases.”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in serum triglyceride levels with partial Rnf145 knockdown.
“We did not observe differences in serum cholesterol or triglyceride levels with this partial Rnf145 knockdown (Figure 7B).”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in serum cholesterol levels with partial Rnf145 knockdown.
“We did not observe differences in serum cholesterol or triglyceride levels with this partial Rnf145 knockdown (Figure 7B).”
Quote in the paperNot a substantial claim - Findingown data
There was no change in liver triglyceride levels in mice transduced with any of the ligases.
“There was no change in serum or liver triglyceride levels in mice transduced with any of the ligases.”
Quote in the paperNot a substantial claim - Findingown data
In liver-specific Scap-/- mice, Rnf145 expression failed to inhibit cholesterologenic gene expression.
“Furthermore, in liver-specific Scap–/– mice, Rnf145 expression failed to inhibit cholesterologenic gene expression (Figure 3H).”
Quote in the paperSubstantial claim - Findingown data
Cholesterol biosynthetic pathway was coordinately upregulated in Rnf145-/- mice compared to controls.
“Unbiased gene ontology and pathway analysis revealed that the cholesterol biosynthetic pathway was coordinately upregulated in Rnf145–/– mice compared to controls (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
GP78 and TRC8 elevated expression of genes involved in both cholesterol and triglyceride production.
“In line with these effects on lipid levels, whereas RNF145 inhibited the expression of cholesterologenic genes, GP78 and TRC8 elevated expression of the genes involved in both cholesterol and triglyceride production (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
SREBP-1 targets recovered over time after RNF145 transduction.
“A more detailed time course of SREBP target gene expression from 2 to 6 days post-RNF145 transduction revealed that both SREBP-1 and SREBP-2 targets were initially suppressed by RNF145, but that SREBP-1 targets recovered over time (Figure 6—figure supplement 1E).”
Quote in the paperNot a substantial claim - Findingown data
Abundance of SCAP protein did not change in response to RNF145 expression.
“Surprisingly, despite the ubiquitination, the abundance of SCAP protein did not change in response to RNF145 expression.”
Quote in the paperSubstantial claim - Findingown data
Expression of GP78 or TRC8 led to an increase in liver cholesterol content.
“Although the expression of RNF145 did not alter cholesterol content in the liver, expression of GP78 or TRC8 led to an increase in liver cholesterol content (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Liver cholesterol levels were not altered in Rnf145-/- mice.
“Liver cholesterol and triglyceride levels, and blood glucose levels were not altered in Rnf145–/– mice (Figure 4B).”
Quote in the paperNot a substantial claim - Findingown data
Administration of GW3965 to both mice and non-human primates induced expression of Rnf145 in liver.
“Administration of GW3965 to both mice and non-human primates induced the expression of Rnf145 in liver (Figure 1B and C).”
Quote in the paperSubstantial claim - Findingown data
The combination of LXR and RXR ligands did not further induce Rnf145 expression.
“The combination of LXR and RXR ligands did not further induce Rnf145 expression.”
Quote in the paperNot a substantial claim - Findingown data
In cells transfected with WT RNF145, sterol depletion-induced processing of SREBP-2 was substantially inhibited.
“In cells transfected with WT RNF145, sterol depletion-induced processing of SREBP-2 was substantially inhibited.”
Quote in the paperSubstantial claim - Findingown data
Liver triglyceride levels were not altered in Rnf145-/- mice.
“Liver cholesterol and triglyceride levels, and blood glucose levels were not altered in Rnf145–/– mice (Figure 4B).”
Quote in the paperNot a substantial claim - Findingown data
There was no change in liver cholesterol content with Rnf145 expression in liver-specific Scap-/- mice.
“There was also no change in liver cholesterol or triglyceride content with Rnf145 expression in liver-specific Scap–/– mice (Figure 3G and Figure 3—figure supplement 1E).”
Quote in the paperSubstantial claim - Findingown data
They were unable to detect an interaction of SCAP and RNF145 in co-immunoprecipitation assays.
“We were unable to detect an interaction of SCAP and RNF145 in co-immunoprecipitation assays (Figure 6—figure supplement 1A), although this finding was not unexpected given the transient interactions between many E3 ubiquitin ligases and their substrates (Harper and Tan, 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Harper and Tan, 2012 source
- Findingown data
Rnf145 expression did not alter serum cholesterol levels in liver-specific Scap-/- mice.
“We found that Rnf145 expression did not alter serum cholesterol or triglyceride levels in liver-specific Scap–/– mice (Figure 3F and Figure 3—figure supplement 1D).”
Quote in the paperSubstantial claim - Findingown data
Stimulation of Rnf145 expression by LXR ligand was lost in primary hepatocytes from LXR DKO mice.
“In contrast, the stimulation of Rnf145 expression by LXR ligand was lost in primary hepatocytes from LXR DKO mice (Figure 1A), indicating that it was dependent on the expression of LXRs.”
Quote in the paperSubstantial claim - Findingown data
Feeding a western diet high in cholesterol prominently induced hepatic expression of Rnf145 in WT C57BL/6 but not Lxrαβ-/- mice.
“Moreover, feeding a western diet high in cholesterol prominently induced hepatic expression of Rnf145 in WT C57BL/6 but not Lxrαβ–/– mice (Figure 1D), indicating that hepatic expression of Rnf145 was responsive to dietary cholesterol in an LXR-dependent manner.”
Quote in the paperSubstantial claim - Findingown data
Sterol depletion of cell culture medium induced efficient SREBP-2 processing, as evidenced by increased accumulation of cleaved nuclear form of SREBP-2.
“Sterol depletion of the cell culture medium induced efficient SREBP-2 processing, as evidenced by increased accumulation of the cleaved nuclear form of SREBP-2 (Figure 6B, Figure 6—figure supplement 1C).”
Quote in the paperSubstantial claim - Findingown data
Expression of RNF145 did not alter cholesterol content in the liver.
“Although the expression of RNF145 did not alter cholesterol content in the liver, expression of GP78 or TRC8 led to an increase in liver cholesterol content (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Endogenous hepatic Rnf145 mRNA expression levels were suppressed by about 40% 6 days post transduction with shRNA.
“Endogenous hepatic Rnf145 mRNA expression levels were suppressed by about 40% 6 days post transduction with shRNA (Figure 7A).”
Quote in the paperSubstantial claim - Findingown data
Expression of genes involved in cholesterol production was substantially inhibited after 6 days in liver tissue of mice transduced with Rnf145.
“In line with this idea, we found that the expression of genes involved in cholesterol production was substantially inhibited after 6 days in the liver tissue of mice transduced with Rnf145 (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Rnf145 overexpression did not affect the membrane-bound precursor form of SREBP-2.
“We found that Rnf145 overexpression reduced the levels of the mature, nuclear form of SREBP-2, without affecting the membrane-bound precursor form (Figure 3I).”
Quote in the paperNot a substantial claim - Findingown data
Blood glucose levels were not altered in Rnf145-/- mice.
“Liver cholesterol and triglyceride levels, and blood glucose levels were not altered in Rnf145–/– mice (Figure 4B).”
Quote in the paperNot a substantial claim - Findingown data
Rnf145 expression did not alter serum triglyceride levels in liver-specific Scap-/- mice.
“We found that Rnf145 expression did not alter serum cholesterol or triglyceride levels in liver-specific Scap–/– mice (Figure 3F and Figure 3—figure supplement 1D).”
Quote in the paperSubstantial claim - Findingown data
Both SREBP-1 and SREBP-2 targets were initially suppressed by RNF145.
“A more detailed time course of SREBP target gene expression from 2 to 6 days post-RNF145 transduction revealed that both SREBP-1 and SREBP-2 targets were initially suppressed by RNF145, but that SREBP-1 targets recovered over time (Figure 6—figure supplement 1E).”
Quote in the paperNot a substantial claim - Findingown data
Expression of mutant Rnf145 (C537A) in liver did not alter cholesterol levels in serum.
“Interestingly, the expression of mutant Rnf145 in liver did not alter cholesterol levels in the serum (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Only expression of RNF145 led to reduced cholesterol levels in serum among RNF145, GP78, TRC8.
“Interestingly, only the expression of RNF145 led to reduced cholesterol levels in the serum (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Chronic inactivation of RNF145 by genetic deletion potentiated expression of cholesterol biosynthetic genes in the liver.
“In this study, both acute suppression of RNF145 via shRNA-mediated knockdown and chronic inactivation of RNF145 by genetic deletion potentiated the expression of cholesterol biosynthetic genes in the liver.”
Quote in the paperSubstantial claim - Findingreasoning
Chronic knockout of Rnf145 did not lead to an elevation of liver cholesterol content.
“For example, acute knockdown of Rnf145 led to an elevation of liver cholesterol content, but this effect was not observed in the chronic knockout model.”
Quote in the paperSubstantial claim - Findingown data
In Rnf145-/- mice with developmental deletion of RNF145, SREBP-2 target genes were selectively upregulated.
“In the setting of developmental deletion loss of RNF145 (Rnf145–/– mice), we observed selective upregulation of SREBP-2 target genes.”
Quote in the paperSubstantial claim - Findingown data
Acute knockdown of Rnf145 led to an elevation of liver cholesterol content.
“For example, acute knockdown of Rnf145 led to an elevation of liver cholesterol content, but this effect was not observed in the chronic knockout model.”
Quote in the paperSubstantial claim - Findingown data
After acute RNF145 expression in the liver, the SREBP-2 pathway remained suppressed.
“We observed suppression of both SREBP-1 and -2 target genes in response to acute RNF145 expression in the liver, but SREBP-1 targets recovered of the course of several days whereas the SREBP-2 pathway remained suppressed.”
Quote in the paperSubstantial claim - Findingown data
SCAP can be ubiquitinated.
“We have extended this work to show that SCAP can also be ubiquitinated.”
Quote in the paperSubstantial claim - Findingown data
RNF145 was the only protein among the E3 ligases tested to reduce serum cholesterol levels when expressed in mouse liver.
“RNF145 was the only protein among the E3 ligases tested to inhibit the expression of genes involved in cholesterol biosynthesis and to reduce serum cholesterol levels when expressed in mouse liver.”
Quote in the paperSubstantial claim - Findingown data
Acute suppression of RNF145 via shRNA-mediated knockdown potentiated expression of cholesterol biosynthetic genes in the liver.
“In this study, both acute suppression of RNF145 via shRNA-mediated knockdown and chronic inactivation of RNF145 by genetic deletion potentiated the expression of cholesterol biosynthetic genes in the liver.”
Quote in the paperSubstantial claim - Findingown data
In this study, SCAP was identified as a direct ubiquitination target of RNF145.
“In this study we identified SCAP, an important regulator of SREBP signaling, as a direct ubiquitination target of RNF145.”
Quote in the paperSubstantial claim - Findingown data
Acute RNF145 expression in the liver suppressed both SREBP-1 and SREBP-2 target genes.
“We observed suppression of both SREBP-1 and -2 target genes in response to acute RNF145 expression in the liver, but SREBP-1 targets recovered of the course of several days whereas the SREBP-2 pathway remained suppressed.”
Quote in the paperSubstantial claim - Findingown data
The effects of acute suppression and chronic inactivation of RNF145 on cholesterol biosynthetic gene expression were only partially overlapping.
“However, the effects of these different manipulations of RNF145 expression were only partially overlapping.”
Quote in the paperSubstantial claim - Findingown data
Ubiquitination of SCAP by RNF145 did not lead to degradation of SCAP in our assays.
“Interestingly, ubiquitination of SCAP by RNF145 did not lead to degradation of SCAP in our assays.”
Quote in the paperSubstantial claim - Findingown data
RNF145 was the only protein among the E3 ligases tested to inhibit the expression of genes involved in cholesterol biosynthesis when expressed in mouse liver.
“RNF145 was the only protein among the E3 ligases tested to inhibit the expression of genes involved in cholesterol biosynthesis and to reduce serum cholesterol levels when expressed in mouse liver.”
Quote in the paperSubstantial claim - Findingown data
After acute RNF145 expression in the liver, SREBP-1 target genes recovered over the course of several days.
“We observed suppression of both SREBP-1 and -2 target genes in response to acute RNF145 expression in the liver, but SREBP-1 targets recovered of the course of several days whereas the SREBP-2 pathway remained suppressed.”
Quote in the paperNot a substantial claim - Interpretationreasoning
This outlines an additional mechanism for coordination of LXR and SREBP actions in lipid homeostasis.
“The demonstration that RNF145 is a functional E3 ligase that modulates SREBP-2 processing through ubiquitination of SCAP outlines an additional mechanism for coordination of LXR and SREBP actions in lipid homeostasis.”
Quote in the paperSubstantial claim - Interpretationown data
Ubiquitination of SCAP on lysine residues K454 and K466 is the basis for RNF145-mediated inhibition of SREBP-2 processing.
“These results suggest that ubiquitination of SCAP on lysine residues K454 and K466 is the basis for RNF145-mediated inhibition of SREBP-2 processing.”
Quote in the paperSubstantial claim - Interpretationown data
Ubiquitination induced by RNF145 does not direct SCAP to degradation.
“These data collectively suggest that the ubiquitination induced by RNF145 does not direct SCAP to degradation.”
Quote in the paperSubstantial claim - Interpretationown data
RNF145 is an integral ER membrane protein.
“These data strongly suggest that RNF145 is an integral ER membrane protein.”
Quote in the paperSubstantial claim - Interpretationown data
Hepatic expression of Rnf145 is responsive to dietary cholesterol in an LXR-dependent manner.
“Moreover, feeding a western diet high in cholesterol prominently induced hepatic expression of Rnf145 in WT C57BL/6 but not Lxrαβ–/– mice (Figure 1D), indicating that hepatic expression of Rnf145 was responsive to dietary cholesterol in an LXR-dependent manner.”
Quote in the paperSubstantial claim - Interpretationown data
RNF145 targets lysine residues K454 and K466 on SCAP for ubiquitination.
“When we transfected the mutant SCAP into CHO cells together with RNF145, we found that the ubiquitination of the mutant SCAP was reduced compared to WT SCAP (Figure 6C), suggesting that RNF145 was targeting these lysine residues.”
Quote in the paperSubstantial claim - Interpretationown data
Endogenous Rnf145 participates in maintenance of cholesterol homeostasis by modulating cholesterol biosynthesis.
“These data suggest endogenous Rnf145 participates in the maintenance of cholesterol homeostasis by modulating cholesterol biosynthesis.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in expression of cholesterologenic genes reflect changes in hepatic cholesterol biosynthesis.
- Interpretationown data
Reduction of serum cholesterol and inhibition of cholesterol biosynthesis by RNF145 requires an intact SREBP signaling pathway.
“These data indicate that reduction of serum cholesterol and inhibition of cholesterol biosynthesis by RNF145 requires an intact SREBP signaling pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in expression of cholesterologenic genes reflect changes in hepatic cholesterol biosynthesis.
- Interpretationown data
LDLR-mediated lipoprotein clearance was not required for effects of RNF145 on hepatic gene expression.
“The expression of cholesterologenic genes was also suppressed by Rnf145 in Ldlr–/– mice (Figure 3—figure supplement 1C), suggesting that LDLR-mediated lipoprotein clearance was not required for these effects of RNF145 on hepatic gene expression.”
Quote in the paperSubstantial claim - Interpretationown data
Rnf145 regulation by LXR is a direct transcriptional effect.
“The regulation of Rnf145 expression by LXR remained intact even with cycloheximide treatment, suggesting that it was a direct transcriptional effect (Figure 1—figure supplement 1).”
Quote in the paperSubstantial claim - Interpretationcitation
Effects of GP78 and TRC8 are consistent with previous reports that they target INSIGs and HMG-CoA reductase for degradation.
“These effects of GP78 and TRC8 are consistent with previous reports that they target INSIGs and HMG-CoA reductase for degradation.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationown data
Rnf145 induction by LXR ligand is dependent on expression of LXRs.
“In contrast, the stimulation of Rnf145 expression by LXR ligand was lost in primary hepatocytes from LXR DKO mice (Figure 1A), indicating that it was dependent on the expression of LXRs.”
Quote in the paperSubstantial claim - Interpretationreasoning
RNF145 action is likely to be more relevant when LXR activators are abundant.
“Therefore, RNF145 action is likely to be more relevant when LXR activators are abundant.”
Quote in the paperNot a substantial claim- Rests on an assumption: Oxysterols inhibit SREBP processing and activate LXRs.
- Rests on an assumption: The relative abilities of specific sterols to regulate SREBP and LXR differ.
- Interpretationown data
RNF145 appears to serve a distinct function in cholesterol homeostasis.
“it appears to serve a very distinct function in cholesterol homeostasis.”
Quote in the paperSubstantial claim - Interpretationown data
The present study has delineated a previously-unrecognized mechanism for ubiquitin-mediated crosstalk between the LXR and SREBP signaling pathways.
“Nevertheless, the present study has delineated a previously-unrecognized mechanism for ubiquitin-mediated crosstalk between the LXR and SREBP signaling pathways and opened up new avenues for future study.”
Quote in the paperSubstantial claim- Rests on an assumption: SCAP is a key regulator of the processing of both SREBP-1 and SREBP-2.
- Interpretationown data
Analysis of Rnf145-/- mice revealed phenotypes associated with RNF145 deficiency not predicted by in vitro models.
“Our analysis of the Rnf145–/– mice has thus revealed phenotypes associated with RNF145 deficiency not predicted by in vitro models.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 38
- It may state two separate claims as one. 17
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe mature SREBP-2 transcription factor translocates to the nucleus where it binds to its target promoters.
“The mature SREBP-2 transcription factor then translocates to the nucleus where it binds to its target promoters (Goldstein et al., 2006).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Goldstein et al., 2006 source
Our copy says that SREBP is processed to its nuclear form in the Golgi and that nuclear SREBP activates genes for cholesterol biosynthesis and uptake (passage 4, labeled Abstract; page unavailable). It also identifies SREBP-2 as an isoform that stimulates cholesterol synthesis (passage 1). These passages support the nuclear transcription-factor role, but do not state that mature SREBP-2 binds its target promoters. (LLM, conf=0.81)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTwo transcription factor families with opposing actions, LXRs and SREBPs, are the main orchestrators of cholesterol homeostasis balance.
“Two transcription factor families with opposing actions – the liver-X receptors (LXRs) and the sterol regulatory element-binding proteins (SREBPs) – are the main orchestrators of this balance (Hong and Tontonoz, 2014; Horton et al., 2002).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Hong and Tontonoz, 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Horton et al., 2002 source
The Abstract identifies SREBPs as regulators of lipid homeostasis and cholesterol synthesis and uptake. The “Transcriptional regulation of SREBP genes” section also discusses LXRs, but describes them as activating SREBP-1c, not as acting in opposition to SREBPs. It does not establish that the two families are the main opposing orchestrators of cholesterol homeostasis. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataRnf145-/- mice were externally unremarkable except for a slightly reduced body weight compared to WT littermates.
“These mice were born at Mendelian ratios and were externally unremarkable except for a slightly reduced body weight compared to WT littermates (Figure 4B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataWT RNF145, but not C537A mutant, induced ubiquitination of SCAP.
“We found that WT RNF145, but not the C537A mutant, induced the ubiquitination of SCAP as evidenced by Western blotting with an antibody against ubiquitin (Figure 6A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataFluorescent signal of tagged RNF145 protein greatly overlapped with ER-resident proteins calnexin and Sec26, but not with Tom20, a mitochondria marker.
“We found that the fluorescent signal of the tagged RNF145 protein greatly overlapped with those of the ER-resident proteins calnexin and Sec26, but not with that of Tom20, a mitochondria marker (Figure 2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataRnf145 expression inhibited SREBP-2 processing in SCAP-knockout cells reconstituted with WT SCAP, but not in those reconstituted with lysine-mutant SCAP.
“Under sterol depletion conditions, we found that Rnf145 expression was able to inhibit SREBP-2 processing in SCAP-knockout cells reconstituted with WT SCAP, but not in those reconstituted with lysine-mutant SCAP (Figure 6D).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataRnf145-/- mice were born at Mendelian ratios.
“These mice were born at Mendelian ratios and were externally unremarkable except for a slightly reduced body weight compared to WT littermates (Figure 4B).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataRnf145 expression retained its ability to lower serum cholesterol levels in Ldlr-/- mice, with magnitude similar to C57BL/6.
“Remarkably, Rnf145 expression retained its ability to lower serum cholesterol levels in Ldlr–/– mice. Indeed, the magnitude of reduction was similar to that observed in C57BL/6 mice.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXRs are nuclear receptors activated by cholesterol metabolite oxysterols in the cell.
“LXRs are nuclear receptors activated by cholesterol metabolite oxysterols in the cell (Fu et al., 2001; Janowski et al., 1996; Lehmann et al., 1997).”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataBoth acute suppression of RNF145 via shRNA-mediated knockdown and chronic inactivation by genetic deletion led to increased hepatic sterol production.
“In sum, both acute suppression of RNF145 via shRNA-mediated knockdown and chronic inactivation of RNF145 by genetic deletion led to increased hepatic sterol production.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in expression of cholesterologenic genes reflect changes in hepatic cholesterol biosynthesis.
It may state two separate claims as one.
Interpretationown dataGain or loss of RNF145 function in mice affects serum cholesterol levels and expression of hepatic genes involved in sterol synthesis.
“Gain or loss of RNF145 function in mice affects serum cholesterol levels and the expression of hepatic genes involved in sterol synthesis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXR inhibits cellular cholesterol uptake in an SREBP-independent fashion through induction of E3 ubiquitin ligase IDOL.
“LXR inhibits cellular cholesterol uptake in an SREBP-independent fashion through the induction of the E3 ubiquitin ligase IDOL (Zelcer et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zelcer et al., 2009 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXR modulates cholesterol biosynthesis in mouse liver by inducing expression of non-coding RNA LeXis.
“LXR was also recently shown to modulate cholesterol biosynthesis in mouse liver by inducing the expression of the non-coding RNA LeXis (Sallam et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sallam et al., 2016 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSREBP-2 preferentially regulates expression of genes involved in cholesterol production.
“SREBP-2 preferentially regulates the expression of genes involved in cholesterol production (Horton et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Horton et al., 2003 source
It may state two separate claims as one.
Interpretationown dataRNF145 is a functional E3 ligase that modulates SREBP-2 processing through ubiquitination of SCAP.
“The demonstration that RNF145 is a functional E3 ligase that modulates SREBP-2 processing through ubiquitination of SCAP outlines an additional mechanism for coordination of LXR and SREBP actions in lipid homeostasis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXR responds to elevated hepatic sterol levels by stimulating fatty acid synthesis through transcriptional induction of Srebp1c expression.
“For example, LXR responds to elevated hepatic sterol levels by stimulating fatty acid synthesis through transcriptional induction of Srebp1c expression (Repa et al., 2000a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Repa et al., 2000a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGP78 and TRC8 have been shown to mediate sterol-induced degradation of HMG-CoA reductase.
“GP78 and TRC8 have been shown to mediate sterol-induced degradation of a rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (Jo et al., 2011; Song et al., 2005).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Jo et al., 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Song et al., 2005 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGP78 degrades INSIG to stimulate SREBP activity.
“GP78 degrades INSIG to stimulate SREBP activity (Liu et al., 2012; Song et al., 2005).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThere are two LXR receptors, LXRα and LXRβ, that share a high degree of functional overlap.
“There are two LXR receptors, LXRα and LXRβ, that share a high degree of functional overlap (Castrillo and Tontonoz, 2004).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Castrillo and Tontonoz, 2004 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationScap knockout mice show reduced nuclear SREBP accumulation and low cholesterol levels in serum and liver.
“Scap knockout mice show reduced nuclear SREBP accumulation and low cholesterol levels in serum and liver (Matsuda et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Matsuda et al., 2001 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAn intronic microRNA located within Srebf2 gene, miR-33, inhibits expression of Abca1.
“Furthermore, an intronic microRNA located within Srebf2 gene, miR-33, inhibits the expression of Abca1 (Najafi-Shoushtari et al., 2010; Rayner et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checkedIt may state two separate claims as one.
Interpretationown dataRNF145 is an LXR- and sterol-induced factor that plays a role in response to elevated hepatic cholesterol load.
“In this study, we identified RNF145 as LXR- and sterol-induced factor that plays a role in the response to elevated hepatic cholesterol load.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn response to elevated cellular cholesterol levels, LXRs induce expression of genes involved in cholesterol efflux, including Abca1, Abcg1 and Apoe.
“In response to elevated cellular cholesterol levels, they function to induce the expression of genes involved in the efflux of cholesterol, including Abca1 and Abcg1 and Apoe (Kennedy et al., 2001; Laffitte et al., 2001; Repa et al., 2000b; Venkateswaran et al., 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataDifferential effects of RNF145 compared to other ER-resident E3 ubiquitin ligases strongly suggested that RNF145 affects sterol metabolism through a distinct mechanism, likely by targeting a distinct protein for ubiquitination.
“The differential effects of RNF145 compared to the other ER-resident E3 ubiquitin ligases strongly suggested that it was affecting sterol metabolism through a distinct mechanism, likely by targeting distinct protein for ubiquitination.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSREBP-2 acts as a positive regulator of Abca1 gene expression by enabling generation of oxysterol ligands for LXR.
“SREBP-2 acts as a positive regulator of Abca1 gene expression by enabling the generation of oxysterol ligands for LXR (Wong et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wong et al., 2006 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenInvestigators were blinded to group allocation for some but not all studies.
“Investigators were blinded to group allocation for some but not all studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationTRC8 reduces stability of SREBP and inhibits SREBP processing in cultured cells.
“TRC8 was reported to reduce the stability of SREBP, and to inhibit SREBP processing in cultured cells (Irisawa et al., 2009; Lee et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation25-hydroxycholesterol is a potent inhibitor of SREBP processing but a weak LXR agonist.
“For example, 25-hydroxycholesterol is a potent inhibitor of SREBP processing but a weak LXR agonist, whereas 22(R)-hydroxycholesterol preferentially activates LXR (Scotti et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Scotti et al., 2011 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXR activation promotes the proteolytic processing of SREBP-1c, but not SREBP-2, by altering membrane phospholipid composition through induction of Lpcat3.
“LXR activation also promotes the proteolytic processing of SREBP-1c, but not SREBP-2, by altering membrane phospholipid composition though induction of Lpcat3 (Rong et al., 2017b).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rong et al., 2017b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationK63 linkages have been associated with non-proteolytic functions.
“In most cases, polyubiquitination of proteins with K48-linked chains often serves to target proteins for degradation by the proteasome (Chau et al., 1989), whereas K63 linkages have been associated with non-proteolytic functions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chau et al., 1989 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenLittermates in all experiments were manually randomized to different treatment groups.
“Littermates in all experiments were manually randomized to different treatment groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSterol LXR ligands generated by the SREBP-2 pathway are required for SREBP-1c pathway activity in the liver.
“Indeed, recent work from Horton and colleagues indicates that sterol LXR ligands generated by the SREBP-2 pathway are actually required for SREBP-1c pathway activity in the liver (Rong et al., 2017a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rong et al., 2017a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLoss of hepatic LXR expression compromises SREBP-1c-dependent lipogenesis.
“LXRs are critical for maximal transcription of SREBP-1c, and loss of hepatic LXR expression therefore compromises SREBP-1c-dependent lipogenesis (DeBose-Boyd et al., 2001; Repa et al., 2000a; Schultz et al., 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationcitationAnalysis of domain structure suggests RNF145 may harbor a sterol-sensing domain, like TRC8.
“analysis of domain structure of RNF145 suggests the protein, like TRC8, may harbor a sterol-sensing domain (Lee et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lee et al., 2010 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPolyubiquitination of proteins with K48-linked chains often serves to target proteins for degradation by the proteasome.
“In most cases, polyubiquitination of proteins with K48-linked chains often serves to target proteins for degradation by the proteasome (Chau et al., 1989), whereas K63 linkages have been associated with non-proteolytic functions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Chau et al., 1989 source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationIncreasing hepatic sterol content leads to decreased SREBP-2 but increased SREBP-1 pathway activity.
“It is known that the interactions of the INSIG-SCAP complex with SREBP-1 and SREBP-2 are differentially sensitive to sterols, as increasing hepatic sterol content leads to decreased SREBP-2 but increased SREBP-1 pathway activity (Repa et al., 2000a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Repa et al., 2000a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe identities of the key endogenous LXR activators in liver remain to be fully determined.
“Unfortunately, as the recent Horton study also makes clear, the identities of the key endogenous LXR activators in liver remain to be fully determined (Rong et al., 2017a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rong et al., 2017a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenSample size was determined based on prior experience with similar in vivo studies.
“Sample size was determined based on prior experience with similar in vivo studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenHEK293T and CHO cells have been previously verified by STR testing and confirmed to be mycoplasma-free by regular testing.
“They have been previously verified by STR testing and were confirmed to be mycoplasma-free by regular testing.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMARCH6 is involved in degradation of squalene epoxidase.
“The ER-resident ubiquitin E3 ligase MARCH6 was shown to be involved in the degradation of squalene epoxidase (Zelcer et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zelcer et al., 2014 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLXRs are critical for maximal transcription of SREBP-1c.
“LXRs are critical for maximal transcription of SREBP-1c, and loss of hepatic LXR expression therefore compromises SREBP-1c-dependent lipogenesis (DeBose-Boyd et al., 2001; Repa et al., 2000a; Schultz et al., 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe shRnf145 plasmids were tested for their ability to inhibit overexpressed Rnf145 in transient transfection experiments in HEK293T cells.
“The resulting pENTR/U6-Rnf145 shRNA plasmids were tested for their ability to inhibit overexpressed Rnf145 in transient transfection experiments in HEK293T cells and then transferred by LR recombination into the pAd/BLOCK-iT-DEST destination vector for viral particle production.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenExperiments were performed at least twice.
“Experiments were performed at least twice.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationThe interactions of the INSIG-SCAP complex with SREBP-1 and SREBP-2 are differentially sensitive to sterols.
“It is known that the interactions of the INSIG-SCAP complex with SREBP-1 and SREBP-2 are differentially sensitive to sterols, as increasing hepatic sterol content leads to decreased SREBP-2 but increased SREBP-1 pathway activity (Repa et al., 2000a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Repa et al., 2000a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Premisecitation22(R)-hydroxycholesterol preferentially activates LXR.
“For example, 25-hydroxycholesterol is a potent inhibitor of SREBP processing but a weak LXR agonist, whereas 22(R)-hydroxycholesterol preferentially activates LXR (Scotti et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Scotti et al., 2011 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSCAP was phosphorylated by the cAMP pathway during steroidogenesis.
“Bornfeldt and colleagues reported that SCAP was phosphorylated by the cAMP pathway during steroidogenesis (Shimizu-Albergine et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Shimizu-Albergine et al., 2016 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationNon-proteolytic ubiquitination via K63 linkage is particularly common in membrane proteins, whose sorting and transport are frequently regulated by this mode of modification.
“Non-proteolytic ubiquitination via K63 linkage is particularly common in membrane proteins, whose sorting and transport are frequently regulated by this mode of modification (Mukhopadhyay and Riezman, 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mukhopadhyay and Riezman, 2007 source
The paper relies on this without support.
Changes in expression of cholesterologenic genes reflect changes in hepatic cholesterol biosynthesis.
“In line with this idea, we found that the expression of genes involved in cholesterol production was substantially inhibited after 6 days in the liver tissue of mice transduced with Rnf145 (Figure 3E).”
“Unbiased gene ontology and pathway analysis revealed that the cholesterol biosynthetic pathway was coordinately upregulated in Rnf145–/– mice compared to controls (Figure 4D).”
The paper relies on this without support.
SCAP is a key regulator of the processing of both SREBP-1 and SREBP-2.
“Since SCAP is a key regulator of the processing of both SREBP-1 and SREBP-2, alterations of SCAP might be expected to affect both SREBP-1 and -2 target genes.”
The paper relies on this without support.
The INSIG-SCAP pathway is the dominant regulator of SREBP-2, especially in the liver.
“It is clear from studies of knockout mice that the INSIG-SCAP pathway is the dominant regulator, especially in the liver.”
The paper relies on this without support.
Oxysterols inhibit SREBP processing and activate LXRs.
“Oxysterols not only inhibit SREBP processing, but also activate LXRs.”
The paper relies on this without support.
The relative abilities of specific sterols to regulate SREBP and LXR differ.
“The relative abilities of specific sterols to regulate SREBP and LXR also differ.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Abstract claims genetic deletion increases liver cholesterol
MajorThe abstract says genetic deletion increases cholesterol in both liver and plasma, but the Results state that liver cholesterol was unchanged in knockout mice.
“Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma.”
“Liver cholesterol and triglyceride levels, and blood glucose levels were not altered in Rnf145–/– mice (Figure 4B).”
Abstract claims acute knockdown increases plasma cholesterol
MinorThe abstract says acute RNF145 suppression increases cholesterol in both liver and plasma, but the Results state that partial knockdown did not change serum cholesterol.
“Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma.”
“We did not observe differences in serum cholesterol or triglyceride levels with this partial Rnf145 knockdown (Figure 7B).”
Knockdown gene-expression finding cites the serum panel
MinorThe text cites Figure 7B for changes in cholesterologenic gene expression, whereas the Figure 7 caption identifies B as serum cholesterol and D as gene expression.
“Furthermore, the expression of a number of cholesterologenic genes was elevated in response to reduced Rnf145 expression, while genes involved in other biological processes, including cholesterol efflux were largely unchanged (Figure 7B).”
“(B) Serum cholesterol levels in mice in A. (C) Cholesterol content in the liver tissue of mice in A. (D) Expression levels of the indicated genes in the liver tissue of mice 6 days after transduction with adenovirus expressing control shRNA or shRNA targeting Rnf145.”
Knockout findings cite the wrong figure
MinorThe knockout serum-cholesterol finding cites Figure 4B and C, but Figure 4 describes adenoviral E3-ligase experiments and has no panel C. The knockout serum and lipoprotein measurements are identified as Figure 8B and C.
“Interestingly, serum cholesterol levels in Rnf145–/– mice were increased in both the LDL and HDL fractions compared to their WT littermates (Figure 4B and C).”
“Figure: Figure 8. Genetic deficiency of Rnf145 affects cholesterol metabolism. (A) Schematic diagram showing the strategy used to generate the Rnf145 knockout mouse line (Rnf145–/–) by CRISPR/Cas9-mediated gene editing. (B) Serum and liver cholesterol levels, liver triglyceride levels, body weight and fasting blood glucose in 4 week-old Rnf145 knockout (Rnf145–/–) mice and WT littermates following a 6 hr fast.”
Citations
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Self-citationSynthetic LXR ligand inhibits the development of atherosclerosis in mice
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Metadata
- Authors
- Zhang, L., Rajbhandari, P., Priest, C., Sandhu, J., Wu, X., Temel, R., Castrillo, A., de Aguiar Vallim, T. Q., Sallam, T., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- University of Kentucky (US)
- Universidad de Las Palmas de Gran Canaria (ES)
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
- Corresponding author
- Tontonoz, Peter
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-10-25
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5656429
- OpenAlex
- W2765999833
- Cited by
- 69
- References
- 52
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 8 · 2021: 7 · 2020: 14 · 2019: 3 · 2018: 10
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- American Heart Association (Scientist Development Grant (16SDG31180008))
- National Heart, Lung, and Blood Institute (HL088528, HL111932)
- National Institutes of Health (HL030568, DK063491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- SCAP, ubiquitination, cholesterol biosynthesis, SREBP2, liver X receptor, cholesterol homeostasis, Golgi transport, serum cholesterol, high-cholesterol diet
- MeSH terms
- Animals, Cholesterol, Gene Expression Regulation, Membrane Proteins, Protein Processing, Post-Translational, Protein Transport, COP-Coated Vesicles, Intracellular Signaling Peptides and Proteins, Mice, Sterol Regulatory Element Binding Protein 2, Ubiquitination, Protein Interaction Maps
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 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (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.
What counts as a claim ›How we measure confidence ›How we check this ›
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