1. Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation
- Author
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Thaddeus T. Schug, Xiumei Guo, Qing Xu, Sailesh Surapureddi, Xiaoling Li, and Aparna Purushotham
- Subjects
endocrine system diseases ,Physiology ,HUMDISEASE ,Peroxisome proliferator-activated receptor ,Endoplasmic Reticulum ,Ligands ,Energy homeostasis ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Sirtuin 1 ,Homeostasis ,Sirtuins ,chemistry.chemical_classification ,0303 health sciences ,Fatty Acids ,Fatty liver ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,medicine.anatomical_structure ,Organ Specificity ,030220 oncology & carcinogenesis ,Hepatocyte ,lipids (amino acids, peptides, and proteins) ,biological phenomena, cell phenomena, and immunity ,Oxidation-Reduction ,hormones, hormone substitutes, and hormone antagonists ,Protein Binding ,Signal Transduction ,Transcriptional Activation ,medicine.medical_specialty ,Biology ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,PPAR alpha ,Molecular Biology ,030304 developmental biology ,Inflammation ,Fatty acid metabolism ,Lipid metabolism ,Feeding Behavior ,Cell Biology ,Lipid Metabolism ,medicine.disease ,Dietary Fats ,Fatty Liver ,enzymes and coenzymes (carbohydrates) ,Endocrinology ,chemistry ,Nuclear receptor ,Hepatocytes ,Trans-Activators ,Steatosis ,Gene Deletion ,Transcription Factors - Abstract
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 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.
- Published
- 2009
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