SIRT1 is a Direct Coactivator of Thyroid Hormone Receptor β1 with Gene-Specific Actions

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 a (PGC-1 alpha), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor beta 1 (TR beta 1) regulates several SIRT1 target genes in liver and interacts with PGC-1 alpha, we hypothesized that SIRT1 may influence TR beta 1. Here, we confirm that SIRT1 cooperates with PGC-1 alpha to enhance response to triiodothyronine, T-3. We also find, however, that SIRT1 stimulates TR beta 1 activity in a manner that is independent of PGC-1 alpha but requires SIRT1 deacetylase activity. SIRT1 interacts with TR beta 1 in vitro, promotes TR beta 1 deacetylation in the presence of T-3 and enhances ubiquitin-dependent TR beta 1 turnover; a common response of NRs to activating ligands. More surprisingly, SIRT1 knockdown only strongly inhibits T-3 response of a subset of TR beta 1 target genes, including glucose 6 phosphatase (G-6-Pc), and this is associated with blockade of TR beta 1 binding to the G-6-Pc promoter. Drugs that target the SIRT1 pathway, resveratrol and nicotinamide, modulate T-3 response at dual TR beta 1/SIRT1 target genes. We propose that SIRT1 is a gene-specific TR beta 1 coregulator and TR beta 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.