Abstract 399: Carnitine Palmitoyltransferase 1a Modulates Hepatic And Lipoprotein Metabolism

Background: Nonalcoholic fatty liver disease (NAFLD) affects almost 1 billion people worldwide and is associated with cardiometabolic risk factors. Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to perturbations in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. The primary goal of this project is to determine the mechanism by which CPT1a alters hepatic and lipoprotein metabolism. Methods: Eight-week-old Cpt1a floxed mice expressing the human APOB100 transgene (Cpt1a fl/fl /B100 Tg ) were administered control adenoassociated virus (AAV) or AAV encoding Cre-recombinase under control of a liver specific promoter (TBG-Cre). Control and LKO mice were placed on low-fat control or western-type diet (WTD; 42% kcal fat, 0.2% cholesterol) for 16 weeks. Livers were collected and used for histological and lipid analysis, while gene and protein expression were measured by single-cell RNA sequencing and immunoblotting, respectively. The lipoprotein composition in plasma was determined by FPLC and nuclear magnetic resonance (NMR). Results: Mice with liver-specific deletion of Cpt1a displayed lower circulating APOB levels consistent with reduced triglyceride rich lipoproteins and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride secretion was enhanced in LKO mice. WTD-feeding elevated hepatic triglycerides in LKO mice across both sexes, while cholesterol (free and esterified) increased by ~2.5-fold specifically in females. Consistent with greater accumulation of free cholesterol in female LKO mice, CD68 + macrophages exhibited increased expression of Mmp12 and Ccl5 , two genes involved in immune cell recruitment and fibrosis. Conclusions: Liver-specific deletion of CPT1a reduces plasma LDL-cholesterol and triglycerides, despite having accelerated VLDL-secretion. Increases in hepatic free cholesterol levels were observed only in female LKO mice, which associates with a pro-inflammatory gene signature in macrophages that may contribute to exacerbation of liver injury in these mice.