Identification of Carnitine Palmitoyltransferase 1a (CPT1a) as a Novel Regulator of Lipoprotein Metabolism

Project Summary: Nonalcoholic fatty liver disease (NAFLD) affects 25% of the world population and is associated with obesity, type II diabetes, and metabolic syndrome. As the leading cause of liver disease, NAFLD increases risk stratification for cardiovascular disease (CVD) resulting in excess morbidity and mortality. To date, pharmaceutical ltirmeaittemde. nVt arerigainmtsenisntacragrentiitningethpearlemsiotoluytlitorannosffeNrAaFseLD1aand(Capsts1oac)i,ataedpCroVtDeinareinevxotlrveemd eilny mitochondrial fatty acid oxidation, have recently been isdheonwtifiethdattolosasssoofciCatpet1awitihn triacylglycerol (TAG) levels in humans. The data herein hepatocytes activates peroxisome proliferator activated receptor α (PPARα) signaling, promotes periportal steatosis, and accelerates very low-density lipoprotein (VLDL)-TAG secretion despite maintaining steady-state serum TAG levels, as compared to control mice. The overarching goal of this proposal is to determine the impact by which the PPARα-CPT1a axis influences VLDL-TAG Cmpett1aabolivliesmr-s,peincsifuiclinknorceksoisutta(nLcKeO, ) and atherosclerosis. Our two specific aims will utilize and littermate control mice to (1) quantify VLDL particle number, size, associated proteins, and clearance rates; and (2) define the role of long chain fatty acid supplementation on PPARα-mediated NAFLD, peripheral TAG hydrolysis, glucose and insulin tolerance, and atherosclerosis. The novelty of the proposed research is the use of tissue-specific KO mice in conjunction with proteomic, nuclear magnetic resonance (NMR), and chromatin uimnmdeurnsotapnrdeicnipgitoaftiwonhyfopllaotwieendtsbywistheqCupetn1caindge(fiCciheInPc-yseeqx)htiebcithanlitqeureeds to establish a better serum TAG profiles while rapidly progressing to liver failure. This research is complimented by a career development plan in which the candidate will learn new experimental methodology, broaden his scientific network through attending workshops and conferences, and develop his communication skills so that he is poised to become a successful principal investigator. This AHA Career Development Award will provide additional research support that allows the applicant to reach his long-term goals of establishing a collaborative and clinically relevant research program focused on identifying novel therapeutics to treat cardiometabolic disease.