COBRE Pilot: Fatty Acid Oxidation in Sexual Dimorphic Obesity and Associated NAFLD

Project Title: Fatty acid oxidation in sexual dimorphic obesity and associated NAFLD Abstract: Nonalcoholic fatty liver disease (NAFLD) affects 25% of the world population and is associated with obesity, type II diabetes, and dyslipidemia. As the leading cause of liver disease, NAFLD increases risk stratification for cardiovascular disease (CVD) resulting in excess morbidity and mortality. Currently, pharmaceutical treatment regimens targeting the resolution of NAFLD and associated CVD are extremely limited. Variants in carnitine palmitoyltransferase 1a (Cpt1a), a protein involved in mitochondrial fatty acid oxidation, have recently been identified to associate with body composition and circulating triacylglycerols in humans. The data herein shows that Cpt1a is abundantly expressed in liver and gonadal white adipose tissue in mice and humans. Moreover, female mice exhibit a greater propensity to undergo hepatic fatty acid oxidation (FAO) and develop exacerbated NAFLD with loss of Cpt1a in hepatocytes, as compared to male mice. The overarching goal of this proposal is to determine the impact of ovarian sex hormones and Cpt1a tissue specificity on obesity and associated NAFLD. Our specific aim will allow a comprehensive examination of the cell autonomous role of Cpt1a in two tissues (hepatocytes, adipocytes) that are critical participants in NAFLD pathophysiology, and will provide data on how ovarian sex hormones impact these roles in each tissue. The novelty of the proposed research is the use of two newly developed liver- and adipocyte-specific Cpt1a deficient mice in conjunction with lipidomics and bulk RNA-sequencing to identify the mechanisms that contribute to Cpt1a-mediated alterations in metabolic disease. This COCVD COBRE pilot award will allow the PI to generate critical preliminary data to support an R01 application to the National Institute of Diabetes and Digestive and Kidney Diseases (PA-20-185) in 2023.