Abstract 437: Carnitine Palmitoyltransferase 1a Modulates Lipoprotein Metabolism

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) affects almost 1 billion people worldwide and is associated with risk factors such as obesity and dyslipidemia. Studies show linked variants and methylation status of carnitine palmitoytransferase 1a (CPT1a) to disrupt very low-density lipoprotein (VLDL) cholesterol and triglyceride (TG) levels. We exhibit liver-specific deletion of CPT1a in mice lowers plasma cholesterol and TG while exacerbating NAFLD and inflammation. Methods: Eight-week old Cpt1a floxed mice with 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 Cpt1a liver-specific knock out (LKO) mice were placed on low-fat control or western-type diet (WTD; 42% kcal fat, 0.2% cholesterol) for 16 weeks. Body weights were recorded weekly and body composition by MRI was performed at the study midpoint and end. Tissues and plasma were collected and analyzed for lipid composition and gene and protein expression by QPCR and immunoblotting, respectively. Results: CPT1a LKO mice had lower plasma cholesterol and TG irrespective of diet. The reduction in plasma cholesterol was limited to the LDL pool in FPLC-fractionated plasma. Hepatic TG was elevated in mice fed WTD and LKO Cpt1a mice. Loss of hepatic Cpt1a had no effect on hepatic cholesterol in male mice, but increased total and free cholesterol by 2- and 2.5-fold, respectively, in females. The rise in hepatic free cholesterol in female Cpt1a LKO mice associated with increases in Kupffer cell ( Clec4f ) and collagen ( Col1a1 ) gene expression. Free cholesterol levels were not related to differences in transcripts for enzymes involved in cholesterol synthesis or secretion ( Srebp2, Hmgcr, Hmgcs, Soat2, Mttp ), hepatic clearance ( Ldlr ), metabolism ( Cpy7a1, Cyp8b1 ), or biliary secretion ( Abcg5, Abcg8 ). Conclusions: Liver-specific deletion of CPT1a reduces plasma LDL-cholesterol and increases cholesterol levels in female, but not male mice. The increase in hepatic free cholesterol did not alter expression of cholesterol-responsive genes, suggesting cholesterol accumulation outside of the regulatory pool.