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A nutrient-sensitive interaction between Sirt1 and HNF-1? regulates Crp expression.

ABSTRACT: Silent information regulator 2 (Sir2) orthologs are an evolutionarily conserved family of NAD-dependent protein deacetylases that regulate aging and longevity in model organisms. The mammalian Sir2 ortholog Sirt1 regulates metabolic and stress responses through the deacetylation of many transcriptional regulatory factors. To elucidate the mechanism by which Sirt1 controls gene expression in response to nutrient availability, we devised a bioinformatic screen combining gene expression analysis with phylogenetic footprinting to identify transcription factors as new candidate partners of Sirt1. One candidate target was HNF-1?, a homeodomain transcription factor that regulates pancreatic ?-cell and hepatocyte functions and is commonly mutated in patients with maturity-onset diabetes of the young (MODY). Interestingly, Sirt1 physically interacts with HNF-1?in vitro but does so in vivo only in nutrient-restricting conditions. This interaction requires 12-24?h of nutrient restriction and is dependent on protein synthesis. Both nutrient restriction and Sirt1 suppress HNF-1? transcriptional activity and the expression of one of its target genes, C-reactive protein (Crp), in mouse primary hepatocytes. Pharmacological inhibition of Sirt1 blocks the suppression of Crp by nutrient restriction. Similarly, Crp expression is also suppressed in fasted and diet-restricted liver. Furthermore, Sirt1 and HNF-1? co-localize on two HNF-1? binding sites on the Crp promoter, leading to decreased acetylation of lysine 16 of histone H4 at these sites only in response to nutrient restriction. These findings reveal a novel nutrient-dependent interaction between Sirt1 and HNF-1? and provide important insight into the molecular mechanism by which Sirt1 mediates the anti-aging effects of diet restriction.

SUBMITTER: Grimm AA

PROVIDER: S-EPMC3079228 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A nutrient-sensitive interaction between Sirt1 and HNF-1α regulates Crp expression.

Grimm Andrew A AA Brace Cynthia S CS Wang Ting T Stormo Gary D GD Imai Shin-ichiro S

Aging cell 20110201 2

Silent information regulator 2 (Sir2) orthologs are an evolutionarily conserved family of NAD-dependent protein deacetylases that regulate aging and longevity in model organisms. The mammalian Sir2 ortholog Sirt1 regulates metabolic and stress responses through the deacetylation of many transcriptional regulatory factors. To elucidate the mechanism by which Sirt1 controls gene expression in response to nutrient availability, we devised a bioinformatic screen combining gene expression analysis wi ...[more]

PMID: 21176092

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Project description:SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported.We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+)-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13].Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions.

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A nutrient-sensitive interaction between Sirt1 and HNF-1? regulates Crp expression.

Publications

A nutrient-sensitive interaction between Sirt1 and HNF-1α regulates Crp expression.

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