Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells.
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 remodeling 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 redirection of lipid synthesis toward 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 channeling both glycerol and fatty acid away from 1,2,3-triacyl-sn-glycerol utilization toward 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 channeling of glycerol and fatty acid precursors into CL.
Xu
Fred Y
FY
Department of Pharmacology and Therapeutics, Center for Research and Treatment of Atherosclerosis and Center on Aging, University of Manitoba, Winnipeg, Canada.
Taylor
William A
WA
Hurd
Jeffrey A
JA
Hatch
Grant M
GM
D000818:Animals; D002308:Cardiolipins / Q000096:biosynthesis* / Q000737:chemistry; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011868:Radioisotopes / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism
D002308:Cardiolipins; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D011868:Radioisotopes; D012694:Serine; D007294:Inositol; C054207:etomoxir; D005990:Glycerol