Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone.

Sirtuin 1 (SIRT1) is a nuclear deacetylase that modulates lipid metabolism and enhances mitochondrial activity. SIRT1 targets multiple transcription factors and coactivators. Thyroid hormone (T3) stimulates the expression of hepatic genes involved in mitochondrial fatty acid oxidation and gluconeogenesis. We reported that T3 induces genes for carnitine palmitoyltransferase (cpt1a), pyruvate dehydrogenase kinase 4 (pdk4), and phosphoenolpyruvate carboxykinase (pepck). SIRT1 increases the expression of these genes via the activation of several factors, including peroxisome proliferator-activated receptor α, estrogen-related receptor α, and peroxisome proliferator-activated receptor γ coactivator (PGC-1α). Previously, we reported that PGC-1α participates in the T3 induction of cpt1a and pdk4 in the liver. Given the overlapping targets of T3 and SIRT1, we investigated whether SIRT1 participated in the T3 regulation of these genes. Resveratrol is a small phenolic compound whose actions include the activation of SIRT1. Addition of resveratrol increased the T3 induction of the pdk4 and cpt1a genes in hepatocytes. Furthermore, expression of SIRT1 in hepatocytes mimicked resveratrol in the regulation of gene expression by T3. The deacetylase activity of SIRT1 was required and PGC-1α was deacetylated following addition of T3. We found that SIRT1 interacted directly with T3 receptor (TRβ). Knockdown of SIRT1 decreased the T3 induction of cpt1a and pdk4 and reduced the T3 inhibition of sterol response element binding protein (srebp-1c) both in isolated hepatocytes and in rat liver. Our results indicate that SIRT1 contributes to the T3 regulation of hepatic genes.