Lipid Storage and the Metablic Syndrome

脂质储存和代谢综合征

• 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
• 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

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.

项目总结（见说明）： 脂质储存对代谢稳态至关重要，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。目的是进一步阐明 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。我们以前的研究表明，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。Lipin-I是一种 磷脂酸磷酸酶（PAP），将磷脂酸转化为二酰基甘油， 脂肪组织和肌肉中的PAP活性。此外，它还是一种转录辅激活因子， 肝脏脂质代谢相关基因的表达。具体目的是：（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中的胰岛素敏感性。在 缺乏lipin-1，磷脂酸在组织中积累，这可能激活信号转导途径 和/或改变线粒体或ER膜特性。我们假设磷脂酸水平 由lipin-1确定的影响PPARgamma表达和脂肪细胞分化，以及胰岛素 肌肉的敏感性。我们将研究lipin-1和磷脂酸水平的失调如何有助于 改变脂肪组织、肌肉和肝脏的代谢。(2)评价Lipin-1在他汀类药物诱导的 肌毒性人类LPINI无义突变导致儿童肌病，错义突变具有 与他汀类药物引起的肌病有关。我们将检验这一假设，即受损的lipin-1活性和 抑制素作用相互作用以损害线粒体功能。我们将在功能上表征突变lipin-1 蛋白质，评估脂蛋白-1缺乏对他汀类药物诱导的小鼠肌毒性的影响，并评估脂蛋白-1缺乏对他汀类药物诱导的小鼠肌毒性的影响。 他汀类药物诱导的LPINI突变肌病受试者队列。(3)识别和表征 新的肥胖基因的分子功能。我们假设，改变肥胖的遗传变异， 将揭示脂肪组织功能的新基因。我们将研究7个候选基因的功能 通过使用体外和体内方法在小鼠中进行网络建模以确定其在脂肪细胞功能中的作用。