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 (TRß). 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.

The minimal Tumor Suppressor in Lung Cancer-1 promoter is restrained by an inhibitory region.

Tumor Suppressor in Lung Cancer-1 (TSLC1) expression is repressed in many different cancers. Hypermethylation of six CpG sites upstream of the TSLC1 coding region is correlated with TSLC1 repression. However, the functional elements of the TSLC1 promoter have not been examined. In this study, the transcription start site was identified as being 67 or 62 bp upstream of the translational start site by primer extension and bioinformatics analysis of expressed sequence tags (ESTs), respectively. Two promoter regions that regulate TSLC1 expression were identified. One, a small region of 170 bp, including 107 bp upstream of the transcription initiation site, is sufficient to generate maximal TSLC1 promoter activity. This minimal promoter does not contain the CpG sites that are hypermethylated in repressed TSLC1 promoters. Two, the maximal activity of the TSLC1 promoter is dampened by an inhibitory region that resides upstream of the minimal promoter.