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Cited by 357Sirtuins and Resveratrol in MedicineCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index; 1 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 access
Walker, Amy K., Yang, Fajun, Jiang, Karen, Ji, Jun-Yuan, Watts, Jennifer L., Purushotham, Aparna, Boss, Olivier, Hirsch, Michael L., Ribich, Scott, Smith, Jesse J., Israelian, Kristine, Westphal, Christoph H., Rodgers, Joseph T., Shioda, Toshi, Elson, Sarah L., Mulligan, Peter, Najafi-Shoushtari, Hani, Black, Josh C., Thakur, Jitendra K., Kadyk, Lisa C., Whetstine, Johnathan R., Mostoslavsky, Raul, Puigserver, Pere, Li, Xiaoling, Dyson, Nicholas J., Hart, Anne C., Näär, Anders M.·2010·Genes & Development
DOI 10.1101/gad.1901210PMC PMC2895199
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Abstract

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.

Overview

AI snapshot

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.

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

Integrity signals

Registry

Crossref · 10.1101/gad.1901210

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

1 of 34 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Findingown data
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    SIRT1 can directly deacetylate SREBP.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    In ob/ob mice fed a high-fat diet, SRT1720 treatment for 4 weeks significantly represses the SREBP-1c gene itself.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Amemiya-Kudo et al. 2000 source
  • Findingown data

    Expression of several NHR-49 target genes (e.g., cpt-4) is unaffected by sir-2.1 deletion during either feeding or fasting.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    Overexpression of wild-type SIRT1 causes strong repression of SREBP target genes in human cells.

    “overexpression of wild-type SIRT1 causes strong repression of SREBP target genes in human cells (Fig. 4D).”
    Quote in the paperSubstantial claim
  • Findingown data

    Nicotinamide, sirtinol, and siRNA-mediated ablation of SIRT1 all increase nuclear abundance of SREBP-1a and SREBP-2 in primary human fibroblasts (IMR-90) and cancer cells (HeLa S).

    “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).”
    Quote in the paperSubstantial claim
    • 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.
  • It may state two separate claims as one. 26
  • Probably not a substantial claim. 16

  • It may state two separate claims as one.

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    SIRT1 protein levels are elevated in the livers of fasted mice and decrease with refeeding.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rodgers and Puigserver 2007 source

      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)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    Modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression.

    “modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    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.

    “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.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Expression of lbp-6 is down-regulated by fasting in wild-type animals, but not in sir-2.1 loss-of-function animals.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nicotinamide treatment of normal human fibroblasts (IMR-90) results in increased levels of endogenous mature (nuclear) SREBP-1 and SREBP-2 proteins, while levels of the precursor proteins are unaffected.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Recently developed SIRT1 activators increase ubiquitination and proteasomal targeting of SREBP-1a, resulting in decreased SREBP-1 nuclear levels and target gene expression.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Milne et al. 2007 source

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

    • cites Feige et al. 2008

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

    • 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.

  • It may state two separate claims as one.

    Findingown data

    The SIR-2.1OE strain 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.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nuclear SBP-1::GFP expression remains high in fasted nematodes carrying a deletion in sir-2.1, or treated with nicotinamide and sirtinol.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Total levels of triglycerides decrease during fasting in wild-type animals, but not in sir-2.1-null animals.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    SRT2183 treatment decreases levels of endogenous mature, nuclear SREBP-1 in cultured cells but has no effect on the SREBP-1 precursor.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Treatment of nematodes with the sirtuin inhibitors nicotinamide and sirtinol results in markedly increased expression of the fat-7p::GFP reporter in the intestine under fasting conditions, while intestinal GFP expression driven by the elt-2 promoter is unaffected.

    “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).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Wild-type SIRT1 deacetylates SREBP-1a in an NAD+-dependent manner, whereas catalytically inactive mutant SIRT1(H363Y) does not.

    “wildtype SIRT1 deacetylates SREBP-1a in an NAD + -dependent manner, whereas the catalytically inactive mutant SIR-T1(H363Y) does not (Fig. 5D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    SBP-1 is required for the expression of endogenous fat-7 in fed and fasted animals, and the accumulation of lipids in fasted sir-2.1-null animals is dependent on SBP-1.

    “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).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The filtering resulted in a nonredundant list of 8573 genes.

    “This resulted in a nonredundant list of 8573 genes.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Raw intensity values of 389,307 features were subjected to a two-tailed t-test (P < 0.05), extracting 13,258 features whose expression significantly differed between SIRT1 knockout and control animals.

    “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.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In C. elegans, fat storage is decreased in wild-type animals upon fasting, but is maintained in fasted sir-2.1(lof) animals.

    “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.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nematodes expressing SBP-1::GFP exhibit strong nuclear fluorescence in intestinal cells of fed animals, whereas fasted animals show markedly reduced nuclear SBP-1::GFP levels.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Horton et al. 1998 source

  • It may state two separate claims as one.

    Findingown data

    mRNA expression of sbp-1 or the NHR-49 target cpt-4 was very modestly altered in sir-2.1(lof) animals.

    “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.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    In cholesterol auxotroph invertebrates such as C. elegans and Drosophila, SREBP homologs primarily regulate fatty acid/lipid homeostasis.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rawson 2003 source
    • cites Osborne and Espenshade 2009 source

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

  • It may state two separate claims as one.

    Interpretationown data
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    SIRT1 orthologs have a conserved role in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    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.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Brown and Goldstein 1997 source
    • cites Osborne and Espenshade 2009 source

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

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage.

    “In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    The mature nuclear forms of SREBP-1 and SREBP-2 are abundant in the mouse liver during feeding, and during fasting SREBPs are markedly down-regulated, correlating with decreased lipogenic and cholesterogenic gene expression.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Horton et al. 1998 source

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

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    SIRT1 orthologs can deacetylate transcription factors such as p53, NF-kB, and E2F.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Haigis and Guarente 2006 source
    • cites Saunders and Verdin 2007 source
    • cites Feige and Auwerx 2008

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

  • Probably not a substantial claim.

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Osborne and Espenshade 2009 source

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

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

    Study design and conductnone given

    More than 30 images from each genotype were scored blind for level of staining in multiple independent experiments.

    “More than 30 images from each genotype were scored blind for level of staining in multiple independent experiments.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation
    § Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Li et al. 2007

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

    • cites Rodgers and Puigserver 2007 source

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

    • cites Pfluger et al. 2008 source

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

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

    Premisecitation

    SIRT1 activators ameliorate insulin resistance and improve energy homeostasis in mouse diet-induced obesity models.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Milne et al. 2007 source

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

  • It may state two separate claims as one.

    Interpretationown data

    The SIRT1 activator SRT2183 impinges on transcriptional programs governing de novo cholesterol/lipid biosynthesis in cultured cells by rendering SREBP susceptible to ubiquitination, decreasing the pool of active SREBP and SREBP-dependent gene expression.

    “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).”
    Quote in the paperSubstantial claim
    • 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.

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

    Premisecitation

    SIRT1 has a well-documented role in stimulation of lipid breakdown in multiple tissues and through several distinct pathways.

    “Indeed, SIRT1 has a well-documented role in stimulation of lipid breakdown in multiple tissues and through several distinct pathways (Yu and Auwerx 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yu and Auwerx 2009 source

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

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

    Premisecitation

    CBP/p300 are regulated by sirtuins, including SIRT1 and SIRT2.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al. 2008 source

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

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

    Premisecitation

    SIRT1 activators increase SIRT1-dependent activation of PGC-1a, FOXO1, and p53, promoting expression of fatty acid b-oxidation genes.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Feige et al. 2008

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

    • cites Smith et al. 2009 source

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

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

    Study design and conductown data

    The absence of systemic bias among samples was confirmed by box plot analysis.

    “The absence of systemic bias among samples was confirmed by the box plot analysis supported by the R statistical programming language.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    SREBP-1c controls its own expression.

    “consistent with the fact that SREBP-1c controls its own expression (Fig. 7E; Amemiya-Kudo et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Amemiya-Kudo et al. 2000 source

  • Probably 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 given

    Cells for photography were selected at random by DAPI staining, and three independent fields were photographed.

    “Cells for photography were selected at random by DAPI staining, and three independent fields were photographed.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    SIRT1 can control the stability of mature, nuclear SREBPs by direct deacetylation.

    “Collectively, these results suggest that SIRT1 can control the stability of mature, nuclear SREBPs by direct deacetylation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The SREBP ortholog in C. elegans, SBP-1, is necessary for lipid production and for expression of multiple lipogenic genes.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites McKay et al. 2003 source

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

    • cites Yang et al. 2006 source

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

    Study design and conductcitation

    Nicotinamide at 25 mM is within the range of physiological effect for SIRT1 in cell culture.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rodgers et al. 2005 source

  • It may state two separate claims as one.

    Interpretationown data

    SIRT1 directly deacetylates SREBP and controls SREBP protein stability.

    “SIRT1 directly deacetylates SREBP and controls SREBP protein stability.”
    Quote in the paperSubstantial claim
39 of 39

  • 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).”
6 of 6

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

    Minor

    The 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.

1 of 1

Citations

Cites

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Research works printed but not linked: 1

  1. 10.1042/0264-6021:3500389 · DOI

Cited by

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Related

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
DOI
10.1101/gad.1901210
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
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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