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CARM1 Function in Hepatic Lipid and Glucose Metabolism

CARM1 在肝脏脂质和葡萄糖代谢中的功能

基本信息

批准号：
8055984
负责人：
Qin Feng
金额：
$ 12.71万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8055984
关键词：
Ablation Aging Animal Model Cells Central obesity Cholesterol Complex Coronary heart disease Country Cultured Cells Development Diet Disease Dyslipidemias Epidemic Fatty Acids Fatty Liver Fatty acid glycerol esters Gene Expression Gene Targeting Generations Genes Genetic Genetic Transcription Glucose Intolerance Health Hepatic Homeostasis Human Hypertension Insulin Resistance Investigation Knockout Mice Knowledge Laboratories Life Style Ligands Liver Liver diseases Mediating Metabolic Metabolic Diseases Metabolic syndrome Molecular Mus Mutant Strains Mice Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nuclear Receptors Peroxisome Proliferator-Activated Receptors Phenotype Play Primary carcinoma of the liver cells RNA RNA Interference Risk Risk Factors Testing United States career coactivator-associated arginine methyltransferase 1 constitutive androstane receptor glucose metabolism lipid metabolism male new therapeutic target non-alcoholic fatty liver novel receptor sedentary small heterodimer partner protein

项目摘要

DESCRIPTION (provided by applicant): 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: Aiml, 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：代谢综合征的特征是一组相关的代谢危险因素，包括腹部肥胖、动脉粥样硬化性血脂异常、高血压、胰岛素抵抗、葡萄糖耐受不良和非酒精性脂肪肝。由于老龄化、高脂肪饮食和久坐的生活方式，代谢综合征在西方国家已成为一种流行病。患有代谢综合征的人患 2 型糖尿病和冠心病的风险显着增加。然而，代谢综合征发生的分子机制仍然很大程度上未知。最近的研究表明，核激素受体，包括过氧化物酶体增殖物激活受体（PPAR）、组成型雄甾烷受体（CAR）、小异二聚体伴侣（SHP）、法尼醇X受体（FXR）和肝脏X受体（LXR），在调节胆固醇、脂肪酸和葡萄糖代谢中发挥着关键作用。小鼠核受体的消融会导致多种代谢紊乱。例如，小鼠体内 FXR 的消融会导致典型的代谢综合征，包括胰岛素抵抗和严重的非酒精性脂肪肝。其他实验室的最新结果和我的初步研究表明，共激活剂相关精氨酸甲基转移酶 1 (CARM1) 是培养细胞中 FXR、LXR 和 PPAR 介导的转录的真正共激活剂。在人肝细胞癌 (HepG2) 细胞中通过小干扰 RNA (siRNA) 敲低 CARM1 会导致相关基因的表达失调葡萄糖和脂质代谢。因此推测CARM1通过选择性调节参与代谢稳态的基因的表达而成为肝脏脂质和葡萄糖代谢的重要调节剂。使用小鼠遗传学方法，该假设将在以下具体目标中得到检验：Aiml，生成肝脏特异性 CARM1 敲除小鼠；目标2，CARM1的鉴定和研究肝脏中的靶基因；目标 3，CARM1 突变小鼠的脂质和葡萄糖代谢分析。由于代谢综合症在美国已成为一种流行病，我的长期职业目标是研究代谢综合症的潜在机制，并寻找针对这种复杂疾病的新治疗方法。公共卫生相关性：代谢综合征及其相关疾病（例如非酒精性脂肪肝）已成为美国的流行病。该提案将利用动物模型研究这些疾病的潜在机制。从拟议的研究中获得的知识可能会揭示 2 型糖尿病、脂肪肝疾病和其他相关代谢性疾病的新治疗靶点。