Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism

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. 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.