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

Helsley, R. N.; Zelows, M.; Noffsinger, V. P.; Anspach, G. B.; Dharanipragada, N.; Mead, A. E.; Cobo, I.; Carter, A.; Wu, Q.; Shalaurova, I.; Saito, K.; Morganti, J. M.; Gordon, S. M.; Graf, G. A.

doi:10.1101/2024.12.13.628437

bioRxiv · 10.1101/2024.12.13.628437

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

Helsley, R. N.·Zelows, M.·Noffsinger, V. P.·Anspach, G. B.·Dharanipragada, N.·Mead, A. E.·Cobo, I.·Carter, A.·Wu, Q.·Shalaurova, I.·Saito, K.·Morganti, J. M.·Gordon, S. M.·Graf, G. A.

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Abstract

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

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Helsley, R. N., Zelows, M., Noffsinger, V. P., Anspach, G. B., Dharanipragada, N., Mead, A. E., Cobo, I., Carter, A., Wu, Q., Shalaurova, I., Saito, K., Morganti, J. M., Gordon, S. M., Graf, G. A.. 2024-12-17. Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice. https://doi.org/10.1101/2024.12.13.628437

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