Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy

lipinl 在骨骼肌线粒体稳态和氧化能量中的作用

• 批准号: 8602575
• 负责人: Hongmei Ren
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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/8602575
• 关键词: Activator Appliances; Acyltransferase; Adipose tissue; Alleles; Animals; Biological Preservation; Blood Pressure; Body Weight; Cardiovascular Diseases; Carnitine; Cell Culture System; Cell Respiration; Cells; Consumption; Defect; Diabetes Mellitus; Diet; Down-Regulation; Embryo; Endoplasmic Reticulum; Energy Metabolism; Enzymes; Equilibrium; Exhibits; Expenditure; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibroblasts; Gene Expression; Genes; Genetic Polymorphism; Glucose; Goals; Hepatic; Homeostasis; Human; Hyperlipidemia; In Vitro; Individual; Link; Lipids; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Morphology; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscle function; Mutation; Myoblasts; Neonatal; Neuropathy; Nuclear; Obese Mice; Obesity; Oxidative Phosphorylation; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphatidate Phosphatase; Phosphoric Monoester Hydrolases; Physiology; Play; Predisposition; Process; Recruitment Activity; Regulation; Research; Respiratory Chain; Respiratory physiology; Rhabdomyolysis; Role; Seminal; Site; Skeletal Muscle; Small Interfering RNA; Surface; System; Tissues; Transcription Coactivator; Transgenic Organisms; Transportation; Triglycerides; Variant; adipocyte differentiation; base; carbohydrate metabolism; fatty acid oxidation; in vivo; insight; insulin sensitivity; lipine; mitochondrial dysfunction; muscle degeneration; muscle metabolism; null mutation; overexpression; oxidation; research study

Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly, preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipinl is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-a responsive genes. Lipinl deficient mice (fatty liver dystrophy mice, fid mice) exhibit impaired adipocyte differentiation, circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipinl is also expressed in skeletal muscle and transgenic overexpression of lipinl in this tissue reverses many ofthe phenotypes of lipinl deficient fid mice. Interestingly, humans with heritable lipinl null mutations present with severe rhabdomyolysis (skeletal, muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity, decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipinl is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids, suggesting that lipinl deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipinl is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly, we hypothesize that recruitment of lipinl to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis, we found mitochondrial respiratory function is impaired in lipinl deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipinl deficient rnice. The broad goal of this research is to define the role of Lipinl in mitochondrial function and skeletal muscle physiology. Aim 1 defines the role of muscle cell lipinl PA phosphatase activity in regulating mitochondrial lipid composition and function, while Aim 2 examines deletion of skeletal muscle lipinl in lean and obese mice.

体重由能量输入和消耗之间的平衡决定。骨骼肌是主要的 脂肪酸和葡萄糖的线粒体氧化代谢位点，因此在 全身能量消耗。因此，保存或促进骨骼肌代谢可以 在防止饮食引起的肥胖方面发挥着关键作用。了解调节机制 骨骼肌代谢及其与控制脂肪储存和动员的关系 因此，这是代谢疾病研究的一个关键目标。 Lipinl 是一种磷脂酸 (PA) 磷酸酶 在细胞质表面催化甘油三酯合成倒数第二步的酶 内质网，也作为 PPAR-a 反应的核转录共激活因子 基因。 Lipinl 缺陷小鼠（脂肪肝营养不良小鼠、fid 小鼠）表现出脂肪细胞分化受损， 循环高脂血症和新生儿肝脂肪变性与肝脂肪率降低相关 酸氧化。 Lipinl 也在骨骼肌中表达，并且在这种情况下 lipinl 的转基因过度表达 组织逆转了脂质缺陷fid小鼠的许多表型。有趣的是，具有遗传性脂质的人类 无效突变表现为严重的横纹肌溶解症（骨骼、肌肉退化），其特征是功能受损 肉碱棕榈酰基转移酶 (CPT) 活性，减少线粒体脂肪氧化和呼吸 链功能和随后的骨骼肌纤维破坏。我们做了开创性的观察 脂质被募集到线粒体表面，促进线粒体裂变和重塑 线粒体脂质，表明脂质缺乏直接影响线粒体功能。基于 根据这些观察结果，我们认为 lipinl 有望发挥脂肪酸和碳水化合物之间的联系作用 肌肉和脂肪的新陈代谢。因此，我们假设脂质直接募集到线粒体 通过影响线粒体稳态来促进线粒体呼吸功能和 β 氧化 和脂质成分，这对于能量代谢中的骨骼肌功能特别重要。 为了直接支持我们的假设，我们发现脂质缺乏症中线粒体呼吸功能受损 从脂质缺陷小鼠的骨骼肌中分离出小鼠胚胎成纤维细胞和线粒体。广义的 这项研究的目标是确定 Lipinl 在线粒体功能和骨骼肌生理学中的作用。 目标 1 定义了肌细胞脂质 PA 磷酸酶活性在调节线粒体脂质中的作用 组成和功能，而目标 2 检查瘦小鼠和肥胖小鼠骨骼肌脂质的缺失。