Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy

体重取决于能量输入和消耗之间的平衡。骨骼肌为主 脂肪酸和葡萄糖的线粒体氧化代谢位点，从而在 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中起关键作用。了解调节的机制 骨骼肌代谢及其与控制脂肪储存和动员的关系， 因此是代谢疾病研究的关键目标。Lipinl是磷脂酸（PA）磷酸酶 一种在细胞质表面催化甘油三酯合成倒数第二步的酶， 内质网，也作为一个核转录共激活因子的PPAR-a反应 基因. Lipinl缺陷型小鼠（脂肪肝营养不良小鼠，FHD小鼠）表现出受损的脂肪细胞分化， 循环性高脂血症和新生儿肝脂肪变性与肝脂肪减少率相关 酸氧化Lipinl也在骨骼肌中表达，并且Lipinl在骨骼肌中的转基因过表达也是如此。 组织逆转了Lipinl缺陷的小鼠的许多表型。有趣的是，患有遗传性血脂异常的人， 无效突变存在于严重横纹肌溶解症（骨骼肌、肌肉变性），其特征为受损 肉毒碱棕榈酰基转移酶（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。我们做了开创性的观察 Lipinl被募集到线粒体表面，在那里它促进线粒体分裂和重塑， 线粒体脂质，表明lipinl缺乏直接影响线粒体功能。基于 根据这些观察，我们认为lipinl是脂肪酸和碳水化合物之间的连接物 肌肉和脂肪的新陈代谢。因此，我们假设lipinl直接募集到线粒体， 促进线粒体呼吸功能和β-氧化通过影响线粒体稳态 和脂质组成，这对骨骼肌在能量代谢中的功能特别重要。 直接支持我们的假设，我们发现线粒体呼吸功能受损的lipinl缺乏， 小鼠胚胎成纤维细胞和从lipinl缺陷rnice的骨骼肌分离的线粒体。广大 本研究的目的是确定Lipinl在线粒体功能和骨骼肌生理学中的作用。 目的1明确肌细胞脂蛋白PA磷酸酶活性在线粒体脂质调节中的作用 目的2检测瘦小鼠和肥胖小鼠骨骼肌脂蛋白1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.