Lipid Storage and the Metablic Syndrome

脂质储存和代谢综合征

基本信息

批准号：
8001177
负责人：
Karen Reue
金额：
$ 43.13万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8001177
关键词：
1,2-diacylglycerol Accounting Adipocytes Adipose tissue Adult Anabolism Biochemical Candidate Disease Gene Central obesity Childhood Cholesterol Cholesterol Homeostasis Collaborations Data Development Diabetes Mellitus Diglycerides Disease Dyslipidemias Energy Metabolism Enzymes Event Fatty Liver Fatty acid glycerol esters Functional disorder Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Goals Heart Diseases Hepatocyte Homeostasis Human In Vitro Instruction Insulin Resistance Knock-out Knowledge Lead Life Lipids Lipodystrophy Lipolysis Liver Membrane Metabolic Metabolic Diseases Metabolic syndrome Metabolism Methods Missense Mutation Mitochondria Molecular Mus Muscle Mutation Myopathy Nonsense Mutation Obesity PPAR gamma Pathway Analysis Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phosphatidate Phosphatase Phosphatidic Acid Phospholipids Physical activity Physiological Play Population Predisposition Process Processed Genes Property Proteins Reducing diet Regulation Research Personnel Risk Role Secondary to Signal Transduction Signal Transduction Pathway Signaling Molecule Skeletal Muscle Symptoms Syndrome System Testing Therapeutic Intervention Tissues Transcription Coactivator Transcriptional Regulation Triglycerides adipocyte differentiation cohort design genetic analysis human disease in vivo insulin sensitivity interest lipid biosynthesis lipid metabolism lipine mouse model mutant network models novel phosphatidate response skeletal trait

项目摘要

PROJECT SUMMARY (See instructions): Lipid storage is critical for metabolic homeostasis, and influences components ofthe metabolic syndrome, including visceral obesity, insulin resistance, and dyslipidemia. The objectives are to further elucidate the function of lipin-1 in lipid synthesis, storage, and lipid signaling in adipose tissue and muscle, and to identify novel genes that influence adipose tissue mass and function. Our previous studies demonstrated that lipin-1 is a determinant of adipose tissue development, insulin sensitivity, and energy metabolism. Lipin-I is a phosphatidate phosphatase (PAP) enzyme that converts phosphatidate to diacylglyerol, and accounts for all PAP activity in adipose tissue and muscle. In addition, it is a transcriptional coactivator that influences expression of lipid metabolism genes in liver. The specific aims are: (1) Determine how lipin-1 modulation of phosphatidate levels regulates adipogenesis and influences insulin sensitivity in skeletal muscle. In the absence of lipin-1, phosphatidate accumulates in tissues, which may activate signal transduction pathways and/or alter mitochondrial or ER membrane properties. We hypothesize that phosphatidate levels determined by lipin-1 influence expression of PPARgamma and adipocyte differentiation, and insulin sensitivity in muscle. We will investigate how dysregulation of lipin-1 and phosphatidate levels contribute to altered metabolism in adipose tissue, muscle, and liver. (2) Evaluate the role of lipin-1 in statin-induced myotoxicity. Human LPINI nonsense mutations cause childhood myopathy, and missense mutations have been associated with statin-induced myopathy. We will test the hypothesis that impaired lipin-1 activity and statin action interact to impair mitochondrial function. We will functionally characterize mutant lipin-1 proteins, evaluate effects of lipin-1 deficiency on statin-induced myotoxicity in the mouse, and evaluate a cohort of subjects with statin-induced myopathy for LPINI mutations. (3) Identify and characterize the molecular function of novel adiposity genes. We hypothesize that genetic variations that alter adiposity in vivo will reveal novel genes in adipose tissue function. We will investigate the function of 7 candidate genes identified by network modeling in the mouse for roles in adipocyte function using in vitro and in vivo methods.

项目摘要（参见说明）：脂质储存对于代谢稳态至关重要，并影响代谢综合征的组成部分，包括内脏肥胖、胰岛素抵抗和血脂异常。目标是进一步阐明 lipin-1 在脂肪组织和肌肉中的脂质合成、储存和脂质信号传导中的功能，并鉴定影响脂肪组织质量和功能的新基因。我们之前的研究表明，lipin-1 是脂肪组织发育、胰岛素敏感性和能量代谢的决定因素。脂质-I 是磷脂酸磷酸酶 (PAP) 将磷脂酸转化为二酰甘油，并解释所有脂肪组织和肌肉中的 PAP 活性。此外，它是一种转录共激活因子，影响肝脏脂质代谢基因的表达。具体目标是：（1）确定lipin-1如何调节磷脂酸水平调节脂肪生成并影响骨骼肌的胰岛素敏感性。在如果缺少 lipin-1，磷脂酸盐会在组织中积聚，这可能会激活信号转导途径和/或改变线粒体或内质网膜特性。我们假设磷脂酸水平通过 lipin-1 影响 PPARgamma 和脂肪细胞分化的表达以及胰岛素确定肌肉的敏感性。我们将研究 lipin-1 和磷脂酸水平的失调如何导致改变脂肪组织、肌肉和肝脏的代谢。 (2) 评价lipin-1在他汀类药物诱导中的作用肌肉毒性。人类 LPINI 无义突变导致儿童肌病，而错义突变则导致儿童肌病与他汀类药物诱发的肌病有关。我们将检验脂质 1 活性受损的假设他汀类药物的作用相互作用，损害线粒体功能。我们将对突变体 lipin-1 进行功能表征蛋白质，评估 lipin-1 缺乏对他汀类药物诱导的小鼠肌肉毒性的影响，并评估患有 LPINI 突变的他汀类药物诱发肌病的受试者队列。 (3) 识别并表征新型肥胖基因的分子功能。我们假设改变肥胖的基因变异体内将揭示脂肪组织功能中的新基因。我们将研究7个候选基因的功能使用体外和体内方法通过小鼠网络模型确定其在脂肪细胞功能中的作用。