Lmf1 in Lapse expression and lipid Metabolism

Lmf1 在Lapse表达和脂质代谢中的作用

• 批准号: 8686033
• 负责人: MIKLOS PETERFY
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8686033
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Affinity; Affinity Chromatography; Alleles; Atherosclerosis; Beta Cell; Binding; Biochemical; Birth; Body Composition; Brain; Cardiomyopathies; Cardiovascular Diseases; Cells; Cessation of life; Cholesterol Homeostasis; Client; Clinical; Code; Collaborations; Collection; Complement; Cytoplasm; DNA Resequencing; Data; Disease; Dyslipidemias; Energy Metabolism; Esterified Fatty Acids; Experimental Designs; Fasting; Fatty Acids; Food; Functional disorder; Gene Expression; Gene Family; General Population; Genes; Genetic; Genetic Determinism; Genotype; Glucose Intolerance; Goals; Grant; HDL-triglyceride; Heart; Heparin; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human Genetics; Hydrolysis; Hypertriglyceridemia; Inbred Strain; Inbred Strains Mice; Individual; Instruction; Insulin Resistance; Investigation; Knockout Mice; Lead; Lipase; Lipids; Lipodystrophy; Lipolysis; Lipoproteins; Mammalian Cell; Metabolic; Metabolic syndrome; Metabolism; Methods; Mexican Americans; Modeling; Molecular; Molecular Genetics; Morphology; Mouse Strains; Mus; Mutation; Nature; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Pancreas; Pathway interactions; Patients; Phenotype; Phospholipids; Physiological; Plasma; Play; Population; Proteins; Proteome; Regulation; Regulator Genes; Reporting; Research; Resources; Role; Skeletal Muscle; Source; Structure; System; Tissues; Triglycerides; Up-Regulation; Variant; Yeasts; adipocyte differentiation; analytical tool; base; cohort; fatty acid metabolism; genetic association; genetic resource; genome wide association study; glucose metabolism; hepatic lipase; insulin secretion; insulin sensitivity; lipid biosynthesis; lipid metabolism; lipoprotein lipase; loss of function; member; metabolic abnormality assessment; mouse model; novel; overexpression; oxidation; tandem mass spectrometry; trait; uptake; yeast two hybrid system

PROJECT SUMMARY (See Instructions): Lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) have long been appreciated as important biochemical players in triglyceride (TG) and cholesterol metabolism. More recently, these lipases emerged as some ofthe strongest genetic determinants of plasma TG and HDL cholesterol levels in the general population. Dysregulation of LPL results in pathological changes associated with the Metabolic Syndrome, including dyslipidemia, insulin resistance, cardiomyopathy and beta-cell dysfunction. Although much ofthe physiological regulation of LPL activity occurs at the post-translational level, the underlying molecular mechanisms have been poorly understood. In the current PPG cycle we identified a novel factor, Lipase Maturation Factor 1 (Lmf1), which facilitates the folding, assembly and secretion of lipases. While Lmf1 is clearly required for lipase expression, the metabolic consequences of combined lipase deficiency in the adult organism, and the molecular function of Lmf1 remain unexplored. Three aims will be pursued to address these issues. In Aim 1, we will generate and characterize conditional and tissue-specific knock-out mouse models to investigate the role of Lmf1 in systemic and adipose metabolism. To extend these studies to humans in Aim 2, we will identify variants associated with fasting or postprandial plasma TG levels by resequencing LMFI in various populations. Furthermore, naturally occurring variants affecting Lmf1 expression in inbred mouse strains will be exploited to address the role of this protein in lipid metabolism and related traits. In Aim 3, we will investigate the molecular aspects of Lmf1 function by identifying the proteome of Lmf1-interacting factors using genetic and biochemical approaches.

项目摘要（参见说明）： 脂蛋白脂肪酶 (LPL)、肝脂肪酶 (HL) 和内皮脂肪酶 (EL) 长期以来一直被认为是 甘油三酯 (TG) 和胆固醇代谢中的重要生化参与者。最近，这些脂肪酶 成为血浆 TG 和 HDL 胆固醇水平的最强遗传决定因素。 一般人群。 LPL 失调会导致与代谢相关的病理变化 综合症，包括血脂异常、胰岛素抵抗、心肌病和β细胞功能障碍。虽然 LPL 活性的大部分生理调节发生在翻译后水平， 分子机制尚不清楚。在当前的 PPG 周期中，我们发现了一个新因素， 脂肪酶成熟因子 1 (Lmf1)，促进脂肪酶的折叠、组装和分泌。尽管 Lmf1 显然是脂肪酶表达所必需的，联合脂肪酶缺乏的代谢后果 Lmf1 的分子功能尚未被探索。将追求三个目标 解决这些问题。在目标 1 中，我们将生成并表征条件性和组织特异性敲除 小鼠模型研究 Lmf1 在全身代谢和脂肪代谢中的作用。为了扩展这些研究 对于目标 2 中的人类，我们将通过以下方式识别与空腹或餐后血浆 TG 水平相关的变异： 对不同人群的 LMFI 进行重新测序。此外，影响 Lmf1 的自然发生的变异 将利用近交系小鼠品系中的表达来解决该蛋白在脂质代谢中的作用 相关特征。在目标 3 中，我们将通过鉴定蛋白质组来研究 Lmf1 功能的分子方面 使用遗传和生化方法研究 Lmf1 相互作用因子。