Mead, A. E. | bioRxiv Science

bioRxiv2024

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

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 CPT1a 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 Cpt1a (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 (PPAR) 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 CPT1a to reductions in circulating apoB-LPs in humans. HIGHLIGHTSO_LILoss-of-function SNPs in CPT1a associate with reductions in plasma cholesterol in humans C_LIO_LIHepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of mice C_LIO_LILiver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle number C_LIO_LICpt1a ablation activates PPAR and favors clearance of apoB-containing lipoproteins C_LI

physiology↗

bioRxiv2023

Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice

Background and AimsGenome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism. Approach and ResultsSix-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid (PUFA) metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. ConclusionsLiver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/553705v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@f42ea0org.highwire.dtl.DTLVardef@12135f2org.highwire.dtl.DTLVardef@15cd9d0org.highwire.dtl.DTLVardef@e0106b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗