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.