Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ

Picard, Frédéric; Kurtev, Martin V.; Chung, Namjin; Topark-Ngarm, Acharawan; Senawong, Thanaset; Oliveira, Rita Machado de; Leid, Mark; McBurney, Michael W.; Guarente, Leonard

doi:10.1038/nature02583

Cited by 1,763 publications

(1,349 citation statements)

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“…Sir2 proteins are also required for the life span-extending effects of caloric restriction (57)(58)(59). NAD biosynthesis plays an important role in regulating Sir2 activity and thereby controls aging, at least in yeast (20,23,24).…”

Section: Discussionmentioning

confidence: 99%

“…Ptn, pleiotrophin; Ptx3, pentaxin-related gene 3; Cxcl1, chemokine (CXC motif) ligand 1; Ccl7, chemokine (CC) motif ligand 7; Gadd45, growth arrest and DNA damage-inducible 45; Atf6, activating transcription factor 6; Ang4, angiopoietin-like 4; Odz4, odd OZ/10-m homolog 4. Fabp4 (fatty acid-binding protein 4), which did not meet the criterion of 95% confidence in Nampt1, was also examined since it is a known target for Sir2 (58). transcriptional repressive activities of GAL4DBD-mCORE in Nampt-overexpressing cells (see "Discussion").…”

Section: Fig 6 Nampt and Sir2␣ Overexpression Induces Common Gene Ementioning

confidence: 99%

“…They have been shown to regulate longevity in yeast (4 -6) and Caenorhabditis elegans (7). In mammals, it has been shown recently that the mammalian Sir2 ortholog, SIRT1/ Sir2␣, plays important roles in a variety of biological processes, such as stress and cytokine responses (8 -12), differentiation (13,14), and metabolism (14), by deacetylating transcriptional regulators. Sir2 proteins possess the unique ability to couple the breakdown of NAD and protein deacetylation to the formation of nicotinamide and O-acetyl-ADP-ribose (15,16).…”

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confidence: 99%

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The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Revollo¹,

Grimm²,

Imai

2004

Journal of Biological Chemistry

853

773

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Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2␣, in mouse fibroblasts. We found that Nampt was the ratelimiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2␣ recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt-and Sir2␣-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2␣ and thereby plays an important role in controlling various biological events in mammals.

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Section: Discussionmentioning

confidence: 99%

Section: Fig 6 Nampt and Sir2␣ Overexpression Induces Common Gene Ementioning

confidence: 99%

mentioning

confidence: 99%

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The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Revollo¹,

Grimm²,

Imai

2004

Journal of Biological Chemistry

853

773

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“…Under low nutrient conditions, up-regulation of SIRT1 promotes hepatic glucose production through interaction and deacetylation of PGC-1␣ (28). Other groups have shown that SIRT1 represses peroxisome proliferator-activated receptor ␥ (PPAR␥) function, increasing lipolysis in white adipose tissue and insulin secretion in pancreatic ␤-cells (29)(30)(31). Interestingly, a nutrient connection to SIRT1 has been previously established in lower eukaryotes, including yeast (32), worms (33), and flies (34).…”

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confidence: 99%

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

Rodgers

Puigserver

2007

Proc. Natl. Acad. Sci. U.S.A.

482

444

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In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1␣ plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1␣. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1␣. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.fasting response ͉ glucose metabolism ͉ lipid metabolism ͉ deacetylase ͉ transcriptional coactivator

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“…Transcriptional repression mediated by the SMRT͞NCoR complex has been found to be important in the regulation of both development and metabolism (8,9), with NCoR null mice exhibiting impaired erythrocyte, thymocyte, and CNS development (10). The repression activity of the SMRT͞NCoR complex is thought to result from the direct or indirect recruitment of three classes of histone deacetylase (HDAC) enzymes, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC7, and SIRT1 (4,6,9,(11)(12)(13)(14). The removal of acetyl groups on the N-terminal tails of histone proteins by these deacetylases is associated with the formation of a repressive chromatin structure in which the accessibility of the DNA template is restricted (15).…”

mentioning

confidence: 99%

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

Codina

Love²,

Li³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a Cterminal SANT (SWI3͞ADA2͞NCoR͞TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.NMR structure ͉ repression ͉ transcription

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Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ

Cited by 1,763 publications

References 29 publications

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

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