Regulation of Mitochondrial Dysfunction and Diet-Induced Obesity by ALCAT1

描述（由申请人提供）：长期目标是阐明有缺陷的心磷脂（CL）代谢导致线粒体功能障碍和氧化应激引起的代谢疾病的分子机制。CL是线粒体氧化磷酸化和ATP合成所需的关键线粒体磷脂。和胆固醇一样，CL也有“好”和“坏”之分，这是由亚油酸的含量决定的。良好CL的侧链以亚油酸为主，而不良CL的侧链则富含长链多不饱和脂肪酸。好与坏CL的比例是由“重塑”过程调节的，该过程包括磷脂酶的去酰化和溶心磷脂酰基转移酶的再酰化。响应活性氧（ROS）的缺陷CL重塑导致不良CL的积累和线粒体功能障碍，最近已被确定为代谢疾病（包括糖尿病、肥胖、心血管疾病和衰老）的常见缺陷。我们最近克隆了第一个酰基转移酶（ALCAT1）参与有缺陷的CL重塑。我们的初步数据表明，ALCAT1在ROS反应的线粒体功能障碍和胰岛素抵抗中起致病作用。本项目旨在验证ALCAT1在氧化应激下的CL重塑缺陷导致线粒体功能障碍并加剧饮食性肥胖代谢并发症的假设。本课题将实现三个目的：1)在C2C12或L6稳定细胞系中，鉴定ALCAT1过表达引起的线粒体功能障碍和胰岛素抵抗的分子缺陷；2)评估ALCAT1缺乏对小鼠饮食性肥胖相关代谢并发症的生理影响；3)确定ALCAT1在CL重塑和磷脂代谢中的调节作用。目前的研究结果有望填补氧化应激引起的线粒体功能障碍与肥胖相关的代谢并发症之间缺失的环节。这项工作也将有助于验证ALCAT1作为糖尿病和肥胖症的新药物靶点，从而激发制药行业对开发代谢性疾病新疗法的兴趣。公共卫生相关性：拟议的工作将有助于确定与肥胖相关的代谢并发症的潜在原因，如糖尿病和心血管疾病。这项研究的结果有望提供关键信息，以确定抑制一种参与不良脂质合成的关键酶是否可以为糖尿病、肥胖和心血管疾病提供一种新的治疗方法。

DESCRIPTION (provided by applicant): The long term goal is to elucidate the molecular mechanisms by which defective cardiolipin (CL) metabolism contributes to the onset of mitochondrial dysfunction and metabolic diseases from oxidative stress. CL is a key mitochondrial phospholipid required for mitochondrial oxidative phosphorylation and ATP synthesis. Like cholesterols, there are "good" and "bad" CL, which is determined by the content of linoleic acid. The side chains of a good CL are dominated by linoleic acid, and a bad CL is enriched with long chain polyunsaturated fatty acids. The ratio of good vs. bad CL is modulated by a "remodeling" process that involves deacylation by phospholipases and reacylation by lysocardiolipin acyltransferases. Defective CL remodeling in response to reactive oxygen species (ROS) leads to accumulation of bad CL and mitochondrial dysfunction which have recently been identified as common defects in metabolic diseases including diabetes, obesity, cardiovascular diseases, and aging. We have recently cloned the first acyltransferase (ALCAT1) involved in defective CL remodeling. Our preliminary data demonstrate that ALCAT1 plays a causative role in mitochondrial dysfunction and insulin resistance in response to ROS. This project is test the hypothesis that defective CL remodeling by ALCAT1 in response to oxidative stress causes mitochondrial dysfunction and exacerbates metabolic complications in diet-induced obesity. The proposal will be accomplished by three Aims: 1) To identify molecular defects in mitochondrial dysfunction and insulin resistance caused by ALCAT1 overexpression in C2C12 or L6 stable cell lines; 2) To assess the physiological effects of ALCAT1 deficiency in mice on metabolic complications associated with diet-induced obesity; and 3) To determine the regulatory role of ALCAT1 in CL remodeling and phospholipid metabolism. Results from the current work are anticipated to fill in a missing link between mitochondrial dysfunction from oxidative stress and onset of metabolic complications associated with obesity. The proposed work will also help to validate ALCAT1 as a novel drug target for diabetes and obesity, and thereby stimulates pharmaceutical industry interests in development of novel treatment for metabolic diseases. PUBLIC HEALTH RELEVANCE: The proposed work will help to identify underlying causes of metabolic complications associated with obesity, such as diabetes and cardiovascular diseases. The results from the proposed research are anticipated to provide key information on whether inhibition of a key enzyme involved in synthesis of a bad lipid can provide a novel treatment of diabetes, obesity, and cardiovascular diseases.