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 (T 3 ) stimulates the expression of hepatic genes involved in mitochondrial fatty acid oxidation and gluconeogenesis. We reported that T 3 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 T 3 induction of cpt1a and pdk4 in the liver. Given the overlapping targets of T 3 and SIRT1, we investigated whether SIRT1 participated in the T 3 regulation of these genes. Resveratrol is a small phenolic compound whose actions include the activation of SIRT1. Addition of resveratrol increased the T 3 induction of the pdk4 and cpt1a genes in hepatocytes. Furthermore, expression of SIRT1 in hepatocytes mimicked resveratrol in the regulation of gene expression by T 3 . The deacetylase activity of SIRT1 was required and PGC-1α was deacetylated following addition of T 3 . We found that SIRT1 interacted directly with T 3 receptor (TRβ). Knockdown of SIRT1 decreased the T 3 induction of cpt1a and pdk4 and reduced the T 3 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 T 3 regulation of hepatic genes. Background: Sirtuin 1 elevates the expression of genes involved in hepatic fatty acid oxidation. Results: Sirtuin 1 modulates the thyroid hormone regulation of the cpt1a , pdk4 , and srebp-1c genes. Conclusion: Sirtuin 1 coregulates the thyroid hormone receptor-mediated induction of gene expression. Significance: Activators of sirtuin 1 and thyroid hormone receptor β agonists could cooperatively stimulate fatty acid oxidation and inhibit lipogenesis.