Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy

体重是由能量输入和消耗之间的平衡决定的。骨骼肌是主要的 线粒体氧化代谢脂肪酸和葡萄糖的部位，从而在 全身能量消耗。因此，保存或促进骨骼肌代谢可以 在预防饮食引起的肥胖方面起着至关重要的作用。了解监管的机制 骨骼肌代谢及其与控制脂肪储存和动员的关系是 因此，代谢性疾病研究的一个关键目标。脂蛋白是一种磷脂酸(PA)磷酸酶 催化甘油三酯合成倒数第二步的酶，在细胞质表面 内质网，也是PPAR-a反应的核转录共激活因子 基因。脂蛋白缺乏的小鼠(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脏脂肪变性与肝脏脂肪减少相关 酸氧化。脂蛋白在骨骼肌中也有表达，转基因脂蛋白在骨骼肌中过表达 组织逆转脂质缺乏的FID小鼠的许多表型。有趣的是，具有可遗传脂类的人类 零突变表现为严重横纹肌溶解(骨骼、肌肉变性)，其特征是受损 肉碱棕榈酰基转移酶(CPT)活性，降低线粒体脂肪氧化和呼吸 链功能和随之而来的骨骼肌纤维的破坏。我们进行了开创性的观察 这种脂素被招募到线粒体表面，在那里它促进线粒体的分裂和重塑 线粒体脂类，提示脂类缺乏直接影响线粒体功能。基于 这些观察结果表明，脂蛋白可能是脂肪酸和碳水化合物之间的纽带。 肌肉和脂肪的新陈代谢。因此，我们假设脂蛋白直接募集到线粒体 通过影响线粒体动态平衡促进线粒体呼吸功能和β-氧化 这对骨骼肌在能量代谢中的功能尤为重要。 为了直接支持我们的假设，我们发现脂质缺乏的人线粒体呼吸功能受损。 小鼠胚胎成纤维细胞和脂质缺乏小鼠骨骼肌分离的线粒体。《博大》 本研究的目的是明确脂蛋白在线粒体功能和骨骼肌生理中的作用。 目的1明确肌细胞脂蛋白PA磷酸酶活性在调节线粒体脂质中的作用 目标2研究瘦小和肥胖小鼠骨骼肌脂蛋白的缺失。

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.