SIRT1 is a direct coactivator of thyroid hormone receptor ?1 with gene-specific actions.

ABSTRACT: Sirtuin 1 (SIRT1) NAD(+)-dependent deacetylase regulates energy metabolism by modulating expression of genes involved in gluconeogenesis and other liver fasting responses. While many effects of SIRT1 on gene expression are mediated by deacetylation and activation of peroxisome proliferator activated receptor coactivator ? (PGC-1?), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor ?1 (TR?1) regulates several SIRT1 target genes in liver and interacts with PGC-1?, we hypothesized that SIRT1 may influence TR?1. Here, we confirm that SIRT1 cooperates with PGC-1? to enhance response to triiodothyronine, T3. We also find, however, that SIRT1 stimulates TR?1 activity in a manner that is independent of PGC-1? but requires SIRT1 deacetylase activity. SIRT1 interacts with TR?1 in vitro, promotes TR?1 deacetylation in the presence of T3 and enhances ubiquitin-dependent TR?1 turnover; a common response of NRs to activating ligands. More surprisingly, SIRT1 knockdown only strongly inhibits T3 response of a subset of TR?1 target genes, including glucose 6 phosphatase (G-6-Pc), and this is associated with blockade of TR?1 binding to the G-6-Pc promoter. Drugs that target the SIRT1 pathway, resveratrol and nicotinamide, modulate T3 response at dual TR?1/SIRT1 target genes. We propose that SIRT1 is a gene-specific TR?1 co-regulator and TR?1/SIRT1 interactions could play important roles in regulation of liver metabolic response. Our results open possibilities for modulation of subsets of TR target genes with drugs that influence the SIRT1 pathway.

SUBMITTER: Suh JH 

PROVIDER: S-EPMC3724829 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature