Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

摘要 线粒体功能障碍是与肥胖及其代谢有关的常见缺陷 并发症。然而，这种功能失调的根本原因仍然难以捉摸。我们的长期目标 旨在阐明线粒体心磷脂(CL)重塑的调控机制 与糖尿病、肥胖症、心血管疾病和衰老相关的功能障碍。这个项目 将阐述ALCAT1调节线粒体活动和能量平衡的假说 通过调节心磷脂中的亚油酸含量来应对氧化应激。这 假设是基于我们的初步结果：1)ALCAT1是定位的线粒体相关的 膜，在那里它催化溶心磷脂的反应。2)过度表达 COS-7细胞中的ALCAT1改善线粒体功能并防止COS-7细胞 氧化应激造成的损害。3)糖尿病大鼠ALCAT1酶活性和mRNA表达上调 以及与氧化应激和心磷脂水平增加相关的肥胖 过氧化。罗格列酮治疗改善线粒体功能并刺激 ALCAT1的表达和酶活性。4)ALCAT1表达缺失的转基因小鼠 能抵抗饮食诱导的肥胖，同时CL中亚油酸含量增加。我们的 假设将在三个具体目标中得到检验。1.确定ALCAT1在调节中的作用 线粒体在氧化应激下的功能。2.研究ALCAT1缺陷如何影响 能量平衡和代谢并发症。3.确定心磷脂的变化和 与ALCAT1缺乏症相关的磷脂谱。当前工作的成果是 有望确定ALCAT1调控作用的分子机制 线粒体功能障碍与糖尿病和肥胖症相关，并验证ALCAT1作为一种 针对代谢性疾病和衰老的药物靶点。

Abstract Mitochondrial dysfunction is a common defect associated with obesity and its metabolic complications. Yet, the underlying causes of the dysfunction remain elusive. Our long term goal is to elucidate the regulatory mechanisms of cardiolipin (CL) remodeling in mitochondrial dysfunctions associated with diabetes, obesity, cardiovascular diseases, and aging. This project will address a hypothesis that ALCAT1 regulates mitochondrial activity and energy homeostasis by modulating linoleic acid content of cardiolipin in response to oxidative stress. This hypothesis is based on our preliminary results that 1) ALCAT1 is localized mitochondriaassociated membrane where it catalyzes reacylation of lysocardiolipin. 2) Overexpression of ALCAT1 in COS-7 cells improves mitochondrial function and prevents the COS-7 cells from damage by oxidative stress. 3) ALCAT1 enzyme activity and mRNA is up-regulated by diabetes and obesity that are associated with an increased level of oxidative stress and cardiolipin peroxidation. Treatment with rosiglitazone improves mitochondrial function and stimulates ALCAT1 expression and enzyme activity. 4) Transgenic mice deficient in ALCAT1 expression are resistant to diet-induced obesity concurrent with increased linoleic acid content in CL. Our hypothesis will be tested in three specific aims. 1. To determine the role of ALCAT1 in regulating mitochondrial function under oxidative stress. 2. To investigate how ALCAT1 deficiency affects energy homeostasis and metabolic complications. 3. To identify changes in cardiolipin and phospholipid profiles associated with ALCAT1 deficiency. Results from the current work is expected to identify molecular mechanisms underlying the regulatory role of ALCAT1 in mitochondrial dysfunction associated with diabetes and obesity, and to validate ALCAT1 as a drug target for metabolic diseases and aging.