The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index; 4 of the 34 sources its claims cite were checked for support.
Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP
Open accessAbstract
The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD+-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis.
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Written from the paper’s full text.
TL;DR
SIRT1 orthologs are required for fasting-dependent down-regulation of SREBP and its lipogenic/cholesterogenic target genes across metazoans. SIRT1 directly deacetylates SREBP, promoting its ubiquitination and turnover, and SIRT1 activators reduce SREBP target expression and hepatosteatosis in obese mice.
Key findings
- In *C. elegans*, fasting decreases intestinal lipids and triglycerides in wild-type animals, but not in *sir-2.1*-null animals; *sir-2.1* loss also prevents fasting-dependent down-regulation of SBP-1 target genes such as *fat-7* and *lbp-6*, while *sir-2.1* overexpression lowers fat storage and target gene expression.
- In *Drosophila*, larvae homozygous for a *dSir2* deletion show increased transcription of dSREBP target genes encoding acetyl-CoA synthase, acetyl-CoA carboxylase, and fatty acid synthase, especially during fasting.
- In mouse liver, SIRT1 shRNA knockdown reduces fasting-dependent down-regulation of FASN, ELOVL6, and SREBP-1c; SIRT1 liver-specific knockout livers show broad up-regulation of SREBP-1 and SREBP-2 targets, including lipogenic and cholesterol biosynthesis genes.
- SIRT1 directly deacetylates SREBP-1a in an NAD+-dependent manner; nicotinamide increases SREBP-1a half-life from ~1 h to ~6 h, and SRT2183 increases SREBP-1a ubiquitination and decreases nuclear SREBP-1. In *ob/ob* mice on high-fat diet, SRT1720 (100 mg/kg daily for 2 or 4 wk) lowers hepatic FASN and SREBP-1c expression at 4 wk and improves hepatosteatosis.
Methods
- Conserved invertebrate assays used *C. elegans* fasting, Sudan Black lipid staining, thin-layer/gas chromatography for triglycerides, qRT-PCR, *sbp-1* RNAi, and GFP reporters for *fat-7* and SBP-1; *Drosophila* Sir2-null third instar larvae were fasted for 24 h and analyzed by qRT-PCR.
- Mammalian experiments used SIRT1 shRNA adenovirus in mouse liver, SIRT1 liver-specific knockout mice, SIRT1 knockout MEFs, human cell lines (HeLa, HEK293T, IMR-90), immunoprecipitation/immunoblotting, immunofluorescence, in vitro deacetylation assays with GST-SIRT1, cycloheximide stability assays, and microarray analysis of SIRT1 LKO livers.
- In vivo SIRT1 activator studies used 6-wk-old *ob/ob* mice fed a high-fat diet, acclimated 2 wk, then dosed with SRT1720 (100 mg/kg) or vehicle by oral gavage daily for 2 or 4 wk (n = 5 per group), with liver lipid extraction and qRT-PCR.
Limitations
- The paper does not include a dedicated limitations section. It notes that the precise mechanistic details of how SIRT1 activators function are still debated (citing Ledford 2008; Pacholec et al. 2010), and that sirtuins may affect multiple metabolic processes, so down-regulation of SREBP activity is described as “a significant contributor” rather than the sole cause of decreased stored lipids.
- The text acknowledges that effects of SIRT1 manipulations could be indirect through CBP/p300, though it reports that immunopurified p300 from SRT2183-treated cells did not show decreased histone acetylation activity.
- It states that it is presently unclear whether AMPK also regulates SREBP in lower metazoans, and that deacetylation may play a minor role in SREBP turnover in nonfasted situations.
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Claims the paper makes
4 of 34 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression.”
- Also stated in: § SIRT1 directly deacetylates SREBP and controls SREBP protein stability · plain
“wildtype SIRT1 deacetylates SREBP-1a in an NAD + -dependent manner, whereas the catalytically inactive mutant SIR-T1(H363Y) does not (Fig. 5D).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § SIRT1 directly deacetylates SREBP and controls SREBP protein stability · plain
In the paper
“We also found that the SREBP-1c gene itself is significantly repressed in response to SRT1720 treatment for 4 wk in these mice, consistent with the fact that SREBP-1c controls its own expression (Fig. 7E; Amemiya-Kudo et al. 2000).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
What the sources say
- Not checked — no full text of the sourcecites Amemiya-Kudo et al. 2000 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the expression of several NHR-49 target genes (e.g., cpt-4) is unaffected by sir-2.1 deletion during either feeding or fasting (Fig. 2C; data not shown).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“overexpression of wild-type SIRT1 causes strong repression of SREBP target genes in human cells (Fig. 4D).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Mammalian SIRT1 represses SREBP-1 and SREBP-2 target gene expression
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that nicotinamide, sirtinol, and siRNA-mediated ablation of SIRT1 all increased the nuclear abundance of SREBP-1a and SREBP-2 in primary human fibroblasts (IMR-90) and cancer cells (HeLa S) (Fig. 6A,B; Supplemental Figs. 7, 8).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Sirtuin inhibition results in increased nuclear SREBP levels
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Nuclear abundance of SREBP isoforms reflects their functional activity.
- Rests on an assumption: RNAi-mediated SIRT1 ablation is specific for SIRT1.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nematodes null for the SIRT1 ortholog sir-2.1 exhibit high levels of lipids under both fed and fasted conditions (Fig. 1A; Supplemental Fig. 1A)”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fasting-dependent decreases in expression of endogenous fat-7 do not occur in sir-2.1(lof)animals.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > p300 HAT assays
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nicotinamide treatment caused a significant increase in acetylation of both overexpressed and endogenous mature forms of SREBPs, consistent with sirtuin regulation of the SREBP acetylation state (Fig. 5A-C).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 directly deacetylates SREBP and controls SREBP protein stability
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“immunopurified p300 from cells treated with SRT2183 does not exhibit decreased activity in terms of acetylation of histones, suggesting that impaired CBP/p300 activity is unlikely to provide an explanation for the observed effects on SREBPs and their target genes (Supplemental Fig. 8).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The SBP-1 target gene lbp-6 is abnormally regulated in the fasting response of sir-2.1(lof)animals.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > p300 HAT assays
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 26
- Probably not a substantial claim. 16
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SIRT1 protein levels are elevated in the livers of fasted mice and decrease with refeeding (Rodgers and Puigserver 2007), a regulatory pattern converse to that of SREBPs.”
What the sources say
- Partly supportedcites Rodgers and Puigserver 2007 sourceExperimental — accuracy not yet measured
The Discussion (p. 5) reports that SIRT1 protein is induced by fasting in mouse liver, supporting the first part of the claim. Our copy does not state that liver SIRT1 protein decreases with refeeding; fed-versus-fasted results elsewhere concern SIRT1’s effects, not that protein-level change. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“knockdown or knockout of SIRT1 in the mouse liver or transgenic overexpression of SIRT1 in mice results in altered lipid/cholesterol levels in serum and the liver (Li et al. 2007;Rodgers and Puigserver 2007;Pfluger et al. 2008;Erion et al. 2009;Purushotham et al. 2009).”
What the sources say
- Not matchedcites Li et al. 2007
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Rodgers and Puigserver 2007 sourceExperimental — accuracy not yet measured
The Results (p. 3) show that hepatic SIRT1 knockdown and overexpression altered serum and liver cholesterol, and that knockdown increased liver free fatty acids. However, this paper used shRNA knockdown and adenoviral overexpression, not knockout or transgenic overexpression; it also found no significant change in serum triglycerides or free fatty acids. (LLM, conf=0.88)
- Partly supportedcites Pfluger et al. 2008 sourceExperimental — accuracy not yet measured
The Results report that Sirt1-transgenic mice had substantially less hepatic lipid accumulation than wild-type mice after 19 weeks on a high-fat diet. But plasma cholesterol and triglyceride levels did not differ between genotypes, and this paper does not report a liver-specific Sirt1 knockdown or knockout lipid result. Thus it supports the hepatic-lipid finding for overexpression, not the full claim attributed to it. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Finally, we show that recently developed SIRT1 activators, which are effective in improving energy homeostasis and decreasing hepatosteatosis in mouse models (Milne et al. 2007;Feige et al. 2008), also increase ubiquitination and proteasomal targeting of SREBP-1a, resulting in decreased SREBP-1 nuclear levels and target gene expression.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Discussion
What the sources say
- Partly supportedcites Milne et al. 2007 sourceExperimental — accuracy not yet measured
The Abstract reports that recently developed SIRT1 activators improved glucose homeostasis and insulin sensitivity in obese mouse models, supporting the metabolic part of the cited parenthetical. Our copy does not report decreased hepatosteatosis. The subsequent SREBP-1a finding is introduced as the citing authors’ own result, not a finding attributed to Milne et al. (LLM, conf=0.86)
- Not matchedcites Feige et al. 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Changes in SREBP target gene expression reflect changes in SREBP transcriptional activity.
- Rests on an assumption: Nuclear abundance of SREBP isoforms reflects their functional activity.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in dietinduced and genetically obese mice.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the expression of lipid-binding protein 6 (lbp-6, a novel SBP-1 target gene) (AK Walker and AM Na ¨a ¨r, unpubl.), is also down-regulated by fasting in wild-type animals, but not in sir-2.1 loss-of-function (lof) animals (Fig. 1F).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nicotinamide treatment of normal human fibroblasts (IMR-90) resulted in increased levels of endoge-nous, mature (nuclear) SREBP-1 and SREBP-2 proteins, while levels of the SREBP-1 and SREBP-2 precursor proteins were unaffected (Fig. 5G, H).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 directly deacetylates SREBP and controls SREBP protein stability
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the SIR-2.1OEstrain exhibits decreased transcription of fat-7 and lbp-6 under both fed and fasted conditions, and has markedly lower intestinal lipid storage as compared with control animals (Fig. 1G,H; Supplemental Fig. 1B; data not shown).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nuclear SBP-1TGFP expression remains high in fasted nematodes carrying a deletion in sir-2.1, or in animals treated with the sirtuin inhibitors nicotinamide and sirtinol (Fig. 2D; Supplemental Fig. 4A; data not shown).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thin-layer chromatography and gas chromatography analyses confirmed that total levels of triglycerides decrease during fasting in wild-type animals, but not in sir-2.1-nullanimals (Fig. 1B).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, SRT2183 treatment decreased the levels of endogenous mature, nuclear SREBP-1 in cultured cells, but had no effect on the SREBP-1 precursor (Fig. 7B,C).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment of nematodes with the sirtuin inhibitors nicotinamide and sirtinol results in markedly increased expression of the fat-7pTGFP reporter in the intestine under fasting conditions, while intestinal GFP expression driven by the elt-2 promoter was unaffected by these treatments, revealing a gene-selective effect of the sirtuin inhibitors (Fig. 1D).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“wildtype SIRT1 deacetylates SREBP-1a in an NAD + -dependent manner, whereas the catalytically inactive mutant SIR-T1(H363Y) does not (Fig. 5D).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 directly deacetylates SREBP and controls SREBP protein stability
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using animals harboring a hypomorphic allele of sbp-1 [sbp-1(ep79)], we also show that SBP-1 is required for the expression of endogenous fat-7 in fed and fasted animals, and that the accumulation of lipids in fasted sir-2.1-nullanimals is dependent on SBP-1 (Fig. 2B; Supplemental Fig. 2A,B).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This resulted in a nonredundant list of 8573 genes.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Microarray experiment and data analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Raw intensity values of 389,307 features were subjected to t-test (P < 0.05, two-tail) to extract 13,258 features whose expression significantly differed between the SIRT1 knockout and control animals.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Microarray experiment and data analysis
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sudan Black staining reveals that fat storage is decreased in wild-type animals upon fasting, but is maintained in fasted sir-2.1(lof)animals.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > p300 HAT assays
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Nematodes expressing a SBP-1TGFP fusion protein driven by the sbp-1 promoter exhibit strong nuclear fluorescence in the intestinal cells of fed animals, whereas fasted animals show markedly reduced nuclear SBP-1TGFP levels, consistent with previously published results in mammals (Fig. 2D; Horton et al. 1998).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
What the sources say
- Not checked yetcites Horton et al. 1998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast with fat-7 expression, mRNA expression of sbp-1 or the NHR-49 target cpt-4 was very modestly altered in sir-2.1(lof)animals.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > p300 HAT assays
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In cholesterol auxotroph invertebrates such as Caenorhabditis elegans and Drosophila melanogaster, SREBP homologs appear to primarily regulate fatty acid/lipid homeostasis (Rawson 2003;Osborne and Espenshade 2009).”
What the sources say
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate here a conserved role for orthologs of the NAD + -dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SREBP family members are controlled in a classic negative feedback manner by the downstream products of the metabolic pathways regulated by SREBPs, such as cholesterol/lipids (Brown and Goldstein 1997;Osborne and Espenshade 2009).”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“The mature nuclear forms of SREBP-1 and SREBP-2 are abundant in the mouse liver during feeding, and the expression of fatty acid and cholesterol biosynthesis genes is high, whereas, during fasting, SREBPs are markedly down-regulated, correlating with decreased lipogenic and cholesterogenic gene expression (Horton et al. 1998).”
What the sources say
- Not checked yetcites Horton et al. 1998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“SIRT1 orthologs not only remove acetyl groups from histone tails, they can also deacetylate transcription factors such as p53, NF-kB, and E2F (Haigis and Guarente 2006;Saunders and Verdin 2007;Feige and Auwerx 2008).”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The sterol regulatory element-binding protein (SREBP) transcription factors represent a highly conserved family of gene regulators controlling key genes involved in the biosynthesis and trafficking of lipids and sterols in eukaryotes from Schizosaccharomyces pombe to humans (Osborne and Espenshade 2009).”
What the sources say
- Not checked yetcites Osborne and Espenshade 2009 source
Checked before — its earlier verdict is held back until a new check runs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Not checked yet
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“More than 30 images from each genotype were scored blind for level of staining in multiple independent experiments.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > C. elegans
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent studies have reported the identification of potent SIRT1-activating compounds, and showed that such SIRT1 activators could significantly ameliorate insulin resistance and improve energy homeostasis in mouse diet-induced obesity models (Milne et al. 2007).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
What the sources say
- Not checked yetcites Milne et al. 2007 source
Checked before — its earlier verdict is held back until a new check runs.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not checked yet
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our work shows that the SIRT1 activator SRT2183 impinges on transcriptional programs governing de novo cholesterol/ lipid biosynthesis in cultured cells by rendering SREBP susceptible to ubiquitination; the resulting proteasomal processing decreases the pool of active SREBP, and, consequently, SREBP-dependent gene expression (Fig. 7A-D).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Changes in SREBP target gene expression reflect changes in SREBP transcriptional activity.
- Rests on an assumption: Nuclear abundance of SREBP isoforms reflects their functional activity.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, SIRT1 has a well-documented role in stimulation of lipid breakdown in multiple tissues and through several distinct pathways (Yu and Auwerx 2009).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Discussion
What the sources say
- Not checked yetcites Yu and Auwerx 2009 source
Checked before — its earlier verdict is held back until a new check runs.
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“CBP/p300 have been reported to be regulated by sirtuins, including SIRT1 and SIRT2 (Liu et al. 2008), and the effects of SIRT1 manipulations that we observe could therefore be indirect.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
What the sources say
- Not checked yetcites Liu et al. 2008 source
Checked before — its earlier verdict is held back until a new check runs.
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not checked yet
None of the sources cited for this claim have been checked yet.
In the paper
“For example, SIRT1 activators increase SIRT1-dependent activation of PGC-1a, FOXO1, and p53, promoting the expression of fatty acid b-oxidation genes (Feige et al. 2008;Smith et al. 2009).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Discussion
What the sources say
- Not matchedcites Feige et al. 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked yetcites Smith et al. 2009 source
Checked before — its earlier verdict is held back until a new check runs.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The absence of systemic bias among samples was confirmed by the box plot analysis supported by the R statistical programming language.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Microarray experiment and data analysis
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“consistent with the fact that SREBP-1c controls its own expression (Fig. 7E; Amemiya-Kudo et al. 2000).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 activators promote inhibition of SREBP target genes, increased SREBP ubiquitination, and decreased SREBP protein stability, and ameliorate aberrant lipogenesis in vivo
What the sources say
- Not checked — no full text of the sourcecites Amemiya-Kudo et al. 2000 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells for photography were selected at random by DAPI staining, and three independent fields were photographed.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Immunoprecipitation, immunoblotting, and immunofluorescence
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these results suggest that SIRT1 can control the stability of mature, nuclear SREBPs by direct deacetylation.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > SIRT1 directly deacetylates SREBP and controls SREBP protein stability
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The SREBP ortholog in C. elegans, SBP-1, is necessary for lipid production and for expression of multiple lipogenic genes (McKay et al. 2003;Yang et al. 2006).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Results
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Nicotinamide (25 mM) treatment was performed for 6-20 h; as noted, this concentration is within the range of physiological effect for SIRT1 in cell culture (Rodgers et al. 2005).”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > Tissue culture
What the sources say
- Not checked — no full text of the sourcecites Rodgers et al. 2005 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SIRT1 directly deacetylates SREBP and controls SREBP protein stability.”
§ Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP > p300 HAT assays
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Changes in SREBP target gene expression reflect changes in SREBP transcriptional activity.
“We also found that treatment of human cell lines with SRT2183 results in significantly decreased expression of SREBP target genes in a dose-dependent manner, consistent with our model (Fig. 7D; data not shown).”
The paper relies on this without support.
Nuclear abundance of SREBP isoforms reflects their functional activity.
“We found that nicotinamide, sirtinol, and siRNA-mediated ablation of SIRT1 all increased the nuclear abundance of SREBP-1a and SREBP-2 in primary human fibroblasts (IMR-90) and cancer cells (HeLa S) (Fig. 6A,B; Supplemental Figs. 7, 8).”
The paper relies on this without support.
FASN is an SREBP target gene.
“Genetically (ob/ob) obese mice fed a high-fat diet and treated with SRT1720 daily for 2 and 4 wk exhibit significantly lower expression of the SREBP target gene FASN in the liver at 4 wk as compared with vehicle-treated mice (Fig. 7E).”
The paper relies on this without support.
Liver weight and hepatic lipid content are valid measures of hepatosteatosis.
“Importantly, ob/ob mice treated with SRT1720 for 4 wk have significantly improved hepatosteatosis, as judged by decreased liver weight and hepatic lipids (Fig. 7F; data not shown).”
The paper relies on this without support.
The ob/ob mouse high-fat diet model is relevant to human metabolic syndrome/hepatosteatosis.
“Genetically (ob/ob) obese mice fed a high-fat diet and treated with SRT1720 daily for 2 and 4 wk exhibit significantly lower expression of the SREBP target gene FASN in the liver at 4 wk as compared with vehicle-treated mice (Fig. 7E).”
The paper relies on this without support.
RNAi-mediated SIRT1 ablation is specific for SIRT1.
“We found that nicotinamide, sirtinol, and siRNA-mediated ablation of SIRT1 all increased the nuclear abundance of SREBP-1a and SREBP-2 in primary human fibroblasts (IMR-90) and cancer cells (HeLa S) (Fig. 6A,B; Supplemental Figs. 7, 8).”
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.
Sirtinol treatment duration differs between methods and figure legend
MinorThe methods specify a 20-hour treatment with 0.1 mM sirtinol, whereas the Figure 4B legend describes a 5-hour treatment at the same concentration.
“Sirtinol (0.1 mM) treatment occurred for 20 h”
“Treatment of human IMR-90 fibroblasts with the sirtuin inhibitors nicotinamide (NAM; 20 mM) or sirtinol (0.1 mM) for 5 h”
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Metadata
- Authors
- Walker, A. K., Yang, F., Jiang, K., Ji, J.-Y., Watts, J. L., Purushotham, A., Boss, O., Hirsch, M. L., Ribich, S., Smith, J. J., Israelian, K., Westphal, C. H., Rodgers, J. T., Shioda, T., Elson, S. L., Mulligan, P., Najafi-Shoushtari, H., Black, J. C., Thakur, J. K., Kadyk, L. C., Whetstine, J. R., Mostoslavsky, R., Puigserver, P., Li, X., Dyson, N. J., Hart, A. C., & Näär, A. M.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Washington State University (US)
- National Institutes of Health (US)
- Exelixis (United States) (US)
- Brown University (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-07-01
- Volume
- 24
- Issue
- 13
- Pages
- 1403-1417
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2895199
- OpenAlex
- W2127088568
- Cited by
- 357
- References
- 74
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 17 · 2023: 24 · 2022: 12 · 2021: 26 · 2020: 30 · 2019: 19 · 2018: 16 · 2017: 15 · 2016: 24 · 2015: 24 · 2014: 36 · 2013: 33 · 2012: 28
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM093072, R01GM053203, R01GM071449)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074114, R01DK088190, R01DK084352, R01DK07833)
- National Center for Research Resources
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- SIRT1, SREBP, fasting, lipid homeostasis, cholesterol homeostasis, protein deacetylation, ubiquitination, protein stability, hepatic lipid synthesis, hepatic steatosis, fat deposition, evolutionary conservation, SIRT1 activators, metabolic syndrome, atherosclerosis
- MeSH terms
- Acetylation, Animals, Benzamides, Cell Line, Cholesterol, Fasting, HeLa Cells, Heterocyclic Compounds, 4 or More Rings, Humans, Lipids, Naphthols, Niacinamide, Down-Regulation, Caenorhabditis elegans, Sirtuins, Mice, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Protein Stability, Sirtuin 1
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.
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