BioProject

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. More...

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates fatty acid metabolism by positively regulating PPAR-alpha. Hepatocyte-specific deletion of SIRT1 impairs PPAR-alpha signaling and decreased fatty acid beta-oxidation in the liver. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis. Overall design: ix Lox control and six Liver-specific SIRT1 KO (SIRT1 LKO) mice in 95% C57BL/6 background were fed ad libitum with free access to water and food. They were then sacrificed at 4:00pm to analyze PPAR-alpha mediated phenotypes under physiologically relevant conditions. Livers from these mice were then dissected and RNA was isolated with a Qiagen RNA easy mini kit with on-column DNAseI treatment. RNA quality was validated with the Agilent 2100 Bioanalyzer in the microarray facility. RNA samples were then pooled with 2 animals/replicate and analyzed by Agilent Whole Mouse arrays. Data are generated by the Rosetta Resolver Error Model. Less...