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

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

• Partly supported

  The ‘SIRT1 substrates in mammals’ section states that SIRT1 deacetylates p53 and NF-κB. The ‘SIRT2’ section also says SIRT1 deacetylates histone H4K16. No passage found in our copy says it deacetylates E2F, so that example is unsupported by this source. (LLM, conf=0.88)

  cites Haigis and Guarente 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Saunders and Verdin 2007 source
• ?Not matched

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

  cites Feige and Auwerx 2008

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 supported

  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)

  cites Rodgers and Puigserver 2007 sourceExperimental — accuracy not yet measured

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 matched

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

  cites Li et al. 2007
• Partly supported

  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)

  cites Rodgers and Puigserver 2007 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Pfluger et al. 2008 sourceExperimental — accuracy not yet measured

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.”

What the sources say

• Partly supported

  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)

  cites Milne et al. 2007 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Feige et al. 2008

In the paper

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

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.”

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).”

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).”

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).”

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).”

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).”

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).”

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).”

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).”

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).”

In the paper

“This resulted in a nonredundant list of 8573 genes.”

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.”

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.”

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).”

What the sources say

• Not checked yetcites Horton et al. 1998 source

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.”

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

• ?Not checked — no full text of the sourcecites Rawson 2003 source
• Not checked yet

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

  cites Osborne and Espenshade 2009 source

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.”

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

• ?Not checked — no full text of the sourcecites Brown and Goldstein 1997 source
• Not checked yet

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

  cites Osborne and Espenshade 2009 source

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.”

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

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 yet

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

  cites Osborne and Espenshade 2009 source

In the paper

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

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).”

What the sources say

• Not checked yet

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

  cites Milne et al. 2007 source

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).”

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).”

What the sources say

• Not checked yet

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

  cites Yu and Auwerx 2009 source

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.”

What the sources say

• Not checked yet

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

  cites Liu et al. 2008 source

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).”

What the sources say

• ?Not matched

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

  cites Feige et al. 2008
• Not checked yet

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

  cites Smith et al. 2009 source

In the paper

“The absence of systemic bias among samples was confirmed by the box plot analysis supported by the R statistical programming language.”

In the paper

“consistent with the fact that SREBP-1c controls its own expression (Fig. 7E; Amemiya-Kudo et al. 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Amemiya-Kudo et al. 2000 source

In the paper

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

In the paper

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

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).”

What the sources say

• Not checked yet

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

  cites McKay et al. 2003 source
• ?Not checked — no full text of the sourcecites Yang et al. 2006 source

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).”

What the sources say

• ?Not checked — no full text of the sourcecites Rodgers et al. 2005 source

In the paper

“SIRT1 directly deacetylates SREBP and controls SREBP protein stability.”