CARM1 Function in Hepatic Lipid and Glucose Metabolism

CARM1 在肝脏脂质和葡萄糖代谢中的功能

• 批准号: 7848080
• 负责人: Qin Feng
• 金额: $ 11.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848080
• 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; Glucose Intolerance; Hepatic; Homeostasis; Human; Hypertension; Insulin Resistance; Investigation; Knockout Mice; Knowledge; Laboratories; Life Style; Ligands; Lipids; 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; public health relevance; receptor; sedentary; small heterodimer partner protein

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、致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、高脂肪饮食和久坐不动的生活方式，代谢综合征已成为西方国家的流行病。代谢综合征患者患2型糖尿病和冠心病的风险显着增加。然而，代谢综合征发展的分子机制在很大程度上仍然未知。最近的研究表明，核激素受体，包括过氧化物酶体激活受体（PPARs），组成型雄烷受体（CAR），小异源二聚体伴侣（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关键作用。小鼠核受体的消融导致多种代谢紊乱。例如，小鼠中FXR的消融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。最近其他实验室的研究结果和我的初步研究表明，辅激活因子相关精氨酸甲基转移酶1（carm 1）是一个真正的辅激活因子FXR，LXR和过氧化物酶体增殖物激活物（PPAR）在培养细胞中介导的转录。在人肝细胞癌（HepG2）细胞中通过小干扰RNA（siRNA）敲低CARM1导致参与葡萄糖和脂质代谢的基因表达失调。因此，假设CARM1通过选择性地调节参与代谢稳态的基因的表达，是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，将在以下特定目标中测试该假设：目标1，产生肝脏特异性CARM1敲除小鼠;目标2，鉴定和研究肝脏中的CARM1靶基因;目标3，分析CARM1突变小鼠中的脂质和葡萄糖代谢。由于代谢综合征在美国已经成为一种流行病，我的长期职业目标是研究代谢综合征的潜在机制，并为这种复杂的疾病寻找新的治疗方法。 公共卫生相关性：代谢综合征及其相关疾病如非酒精性脂肪肝在美国已成为流行病。本研究拟通过动物模型探讨这些疾病的发病机制。从拟议的研究中获得的知识可能会揭示2型糖尿病，脂肪肝和其他相关代谢疾病的新治疗靶点。