Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells

Fred Y Xu, William A Taylor, Jeffrey A Hurd, and Grant M Hatch

Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E 0T6

Corresponding Author: hatchgm{at}ms.umanitoba.ca

We examined the effect of etomoxir-treatment on de novo cardiolipin (CL) biosynthesis in H9c2 cardiac myoblast cells. Etomoxir-treatment did not affect the activities of the CL biosynthetic and remodelling enzymes but caused a reduction in [1-14C]palmitic acid or [1-14C]oleic acid incorporation into CL. The mechanism was a decrease in fatty acid flux through the de novo pathway of CL biosynthesis via a re-direction of lipid synthesis towards 1,2-diacyl-sn-glycerol utilizing reactions mediated by a 35% increase (p<0.05) in membrane phosphatidate phosphohydrolase activity. In contrast, etomoxir-treatment increased [1,3-3H]glycerol incorporation into CL. The mechanism was a 33% increase (p<0.05) in glycerol kinase activity which produced an increased glycerol flux through the de novo pathway of CL biosynthesis. Etomoxir-treatment inhibited 1,2-diacyl-sn-glycerol acyltransferase activity by 81% (p<0.05) thereby channelling both glycerol and fatty acid away from 1,2,3-triacyl-sn-glycerol utilization towards phosphatidylcholine and phosphatidylethanolamine biosynthesis. In contrast, etomoxir inhibited myo-[3H]inositol incorporation into phosphatidylinositol and the mechanism was an inhibition in inositol uptake. Etomoxir did not affect [3H]serine uptake but resulted in an increased formation of phosphatidylethanolamine derived from phosphatidylserine. The results indicate that etomoxir-treatment has diverse effects on de novo glycerolipid biosynthesis from various metabolic precursors. In addition, etomoxir mediates a distinct and differential metabolic channelling of glycerol and fatty acid precursors into CL.

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