Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice.

UNLABELLED

Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride (VLDL-TG) and cholesterol (VLDL-C) secretion rates are increased, suggesting accelerated clearance of apoB-containing lipoproteins (apoB-LPs) in LKO mice. Mechanistic approaches show greater peroxisome proliferator activated receptor α (PPARα) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in ApoCII and ApoAIV and reductions in ApoCIII & Angptl3. These studies provide mechanistic insight linking genetic variants and methylation status of to reductions in circulating apoB-LPs in humans.

HIGHLIGHTS

Loss-of-function SNPs in associate with reductions in plasma cholesterol in humans Hepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of miceLiver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle numberCpt1a ablation activates PPARα and favors clearance of apoB-containing lipoproteins.