Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice

作者：Robert N. Helsley, Mikala Zelows, Victoria P. Noffsinger, Garrett Anspach, Nikitha Dharanipragada, Anna E. Mead, Isidoro Cobo, Abigail Carter, Qinglin Wu, Irina Shalaurova, Kai Saito, Josh M. Morganti, Scott M. Gordon, Gregory A. Graf · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2025 · DOI：10.1161/atvbaha.125.322473 · 被引用次数：6 · 研究领域：Metabolism and Genetic Disorders、Diabetes, Cardiovascular Risks, and Lipoproteins、Peroxisome Proliferator-Activated Receptors

BACKGROUND: Genome- and epigenome-wide association studies have associated variants and methylation status of CPT1a (carnitine palmitoyltransferase 1a) to reductions in VLDL (very low-density lipoprotein) cholesterol and triglyceride levels. The objective of this study was to determine the mechanisms by which CPT1a-dependent mitochondrial fatty acid oxidation influences hepatic and lipoprotein metabolism. METHODS: Eight-week-old male and female Cpt1a -floxed mice ( Cpt1a fl/fl ) and Cpt1a -floxed mice expressing the human apo B 100 transgene ( Cpt1a fl/fl /B100 Tg ) were administered control adeno-associated virus or adeno-associated virus encoding Cre-recombinase under control of a liver-specific promoter (TBG-Cre [thyroxin-binding globulin]). Control and liver-specific knockout mice were placed on a low-fat control or western-type diet (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 bulk RNA-sequencing and immunoblotting, respectively. Lipoprotein composition in plasma was determined by size exclusion chromatography and nuclear magnetic resonance. Rates of VLDL-triglyceride secretion were quantified after lipase inhibition with poloxamer 407. Liquid and gas chromatography–mass spectrometry were used to measure bile acid species and fecal neutral sterols, respectively. RESULTS: We report significant associations between the presence of CPT1a SNPs (single nucl...