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.
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.
|Chen, Fang; Sha, Min; Wang, Yanyang et al. (2016) Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models. Diabetologia 59:316-24|
|Li, Ling; Gao, Lin; Wang, Kejia et al. (2016) Knockin of Cre Gene at Ins2 Locus Reveals No Cre Activity in Mouse Hypothalamic Neurons. Sci Rep 6:20438|
|Cao, Dongmei; Ma, Xianhua; Cai, Jiao et al. (2016) ZBTB20 is required for anterior pituitary development and lactotrope specification. Nat Commun 7:11121|
|Liu, Ying; Takahashi, Yoshinori; Desai, Neelam et al. (2016) Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin resistance. Sci Rep 6:20453|
|(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Hsu, Paul; Liu, Xiaolei; Zhang, Jun et al. (2015) Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy. Autophagy 11:643-52|
|Wang, Li; Liu, Xiaolei; Nie, Jia et al. (2015) ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology 61:486-96|
|Zhang, Jun; Xu, Dan; Nie, Jia et al. (2015) Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase. J Biol Chem 290:241|
|Zhou, Xiu; Xu, Jun; Shi, Yuguang et al. (2015) Discovery of Novel Anti-Diabetic Drugs by Targeting Lipid Metabolism. Curr Drug Targets 16:1372-80|
|Zhang, Jun; Xu, Dan; Nie, Jia et al. (2014) Monoacylglycerol acyltransferase-2 is a tetrameric enzyme that selectively heterodimerizes with diacylglycerol acyltransferase-1. J Biol Chem 289:10909-18|
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