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Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation Purushotham A; Schug TT; Xu Q; Surapureddi S; Guo X; Li XCell Metab 2009[Apr]; 9 (4): 327-38Hepatic 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 lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. 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 and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.|*Gene Deletion[MESH]|Animals[MESH]|Dietary Fats/administration & dosage/pharmacology[MESH]|Endoplasmic Reticulum/drug effects/pathology[MESH]|Fatty Acids/*metabolism[MESH]|Fatty Liver/*complications/*enzymology[MESH]|Feeding Behavior/drug effects[MESH]|Hepatocytes/drug effects/*enzymology[MESH]|Homeostasis/drug effects[MESH]|Inflammation/*complications/enzymology[MESH]|Ligands[MESH]|Lipid Metabolism/drug effects[MESH]|Mice[MESH]|Organ Specificity/drug effects[MESH]|Oxidation-Reduction/drug effects[MESH]|PPAR alpha/metabolism[MESH]|Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha[MESH]|Protein Binding/drug effects[MESH]|Signal Transduction/drug effects[MESH]|Sirtuin 1[MESH]|Sirtuins/*genetics/metabolism[MESH]|Trans-Activators/metabolism[MESH]|Transcription Factors[MESH]|Transcriptional Activation/drug effects[MESH] |
