Metabolic syndrome is characterized by a group of related metabolic risk factors, including abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, glucose intolerance, and nonalcoholic fatty liver. Metabolic syndrome has become an epidemic in western countries due to aging, high-fat diets and sedentary lifestyle. People with Metabolic Syndrome are at a significantly increased risk for type 2 diabetes and coronary heart disease. However the molecular mechanisms of metabolic syndrome development remain largely unknown. Recent studies demonstrate that nuclear hormone receptors, including Peroxisome Proliferator-Activated Receptors (PPARs), Constitutive Androstane Receptor (CAR), Small Heterodimer Partner (SHP), Farnesoid X receptor (FXR), and Liver X receptor (LXR), play critical functions in regulating cholesterol, fatty acid, and glucose metabolism. Ablation of nuclear receptors in mice results in multiple metabolic disorders. For instance, ablation of FXR in mice causes the typical metabolic syndrome including insulin resistance and severe nonalcoholic fatty liver. Recent results from other laboratories and my preliminary study demonstrate that coactivator associated arginine methyltransferase 1 (CARM1) is a bona fide coactivator for FXR, LXR and PPAR(-mediated transcription in the cultured cells. Knockdown of CARM1 by small interference RNA (siRNA) in human hepatocellular carcinoma (HepG2) cells results in deregulated expression of genes involved in glucose and lipid metabolism. It is thus hypothesized that CARM1 is an important regulator of hepatic lipid and glucose metabolism by selectively modulating the expression of genes involved in metabolic homoeostasis. Using mouse genetic approaches, this hypothesis will be tested in the following specific aims:
Aim l, generation of liver-specific CARM1 knockout mice;
Aim 2, identification and investigation of CARM1 target genes in the liver;
Aim 3, analysis of lipid and glucose metabolism in CARM1 mutant mice. Since Metabolic Syndrome has become an epidemic in the United States, my long-term career objective is to study the underlying mechanism of metabolic syndrome and look for novel treatment for this complex disease.
Metabolic Syndrome and its related disorders such as nonalcoholic fatty liver disease have become an epidemic in the United States. This proposal will investigate the underlying mechanisms of these diseases using the animal models. The knowledge derived from the proposed study may reveal novel therapeutic targets for type 2 diabetes, fatty liver disease, and other related metabolic disorders.
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