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. 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. Cardiolipin (CL) is a major membrane phospholipid in most mammalian cells and is localized primarily to the inner mitochondrial membrane where it comprises approximately 20% of the mitochondrial phospholipid mass (1Hostetler K.Y. Polyglycerophospholipids: phosphatidylglycerol, diphosphatidylglycerol and bis(monoacylglycerol)phosphate.in: Hawthorne J.N. Ansell G.B. Phospholipids. Elsevier Press, Amsterdam1982: 215-261Google Scholar, 2Daum G. Lipids of mitochondria.Biochim. Biophys. Acta. 1985; 882: 1-42Google Scholar, 3Poorthuis B.J. Yazaki P.J. Hostetler K.Y. An improved two-dimensional thin layer chromatrography system for the separation of phosphatidylglycerol and its derivatives.J. Lipid Res. 1976; 17: 433-437Google Scholar). In addition, CL has been identified in the outer mitochondrial membrane (4Hovius R. Lambrechts H. Nicolay K. de Kruijff B. Improved methods to isolate and subfractionate rat liver mitochondria. Lipid composition of the outer mitochondrial membrane.Biochim. Biophys. Acta. 1990; 1021: 217-226Google Scholar, 5Hovius R. Thijssen J. van der Linden P. Nicolay K. de Kruijff B. Phospholipid asymmetry of the outer membrane of rat liver mitochondria. Evidence for the presence of cardiolipin on the outside of the outer membrane.FEBS Lett. 1993; 330: 71-76Google Scholar). CL was shown to be required for the reconstituted activity of a number of key mammalian mitochondrial enzymes involved in cellular energy metabolism (6Vik S.B. Georgevich G. Capaldi R.A. Diphosphatidylglycerol is required for optimal activity of beef heart cytochrome c oxidase.Proc. Natl. Acad. Sci. USA. 1981; 78: 1456-1460Google Scholar, 7Fiol C.J. Bieber L.L. Sigmoidal kinetics of purified beef heart mitochondrial carnitine palmitoyltransferase.J. Biol. Chem. 1984; 259: 13084-13088Google Scholar, 8Muller M. Moser R. Cheneval D. Carafoli E. Cardiolipin is the membrane receptor for creatine phosphokinase.J. Biol. Chem. 1985; 260: 3839-3843Google Scholar, 9Hutson S.M. Roten S. Kaplan R.S. Solubilization and reconstitution of the branched-chain-alpha-keto acid transporter from rat heart mitochondria.Proc. Natl. Acad. Sci. USA. 1990; 87: 1028-1031Google Scholar, 10Kaplan R.S. Mayor J.A. Johnston N. Oliveira D.L. Purification and characterization of the reconstitutively active tricarboxylate transporter from rat liver mitochondria.J. Biol. Chem. 1990; 265: 13379-13385Google Scholar, 11Belezani Z.S. Janesik V. Role of cardiolipin in the function of the L-glycerol-3-phosphate dehydrogenase.Biochem. Biophys. Res. Commun. 1989; 159: 132-139Google Scholar, 12Kadenbach B. Mende P. Kolbe H.V. Stipani I. Palmieri F. The mitochondrial phosphate carrier has an essential requirement for cardiolipin.FEBS Lett. 1982; 139: 109-112Google Scholar, 13Hoffman B. Stockl A. Schlame M. Beyer K. Klingenberg M. The reconstituted ADP/ATP carrier activity has an absolute requirement for cardiolipin as shown in cysteine mutants.J. Biol. Chem. 1994; 269: 1940-1944Google Scholar, 14Eble K.S. Coleman W.B. Hantgan R.R. Cunningham C.C. Tightly associated cardiolipin in bovine heart mitochondrial ATP synthase as analysed by 31P nuclear magnetic resonance spectroscopy.J. Biol. Chem. 1990; 265: 19434-19440Google Scholar). More recently, peroxidation of CL in mitochondria of rat basophile leukemia cells resulted in dissociation of cytochrome c from mitochondrial inner membranes, an initial step in cytochrome c-mediated apoptosis (15Nomura K. Imai H. Koumura T. Kobayashi T. Nakagawa Y. Mitochondrial hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycemia-induced apoptosis.Biochem. J. 2000; 351: 183-193Google Scholar). In mammalian tissues, CL contains four fatty acid side chains occupied primarily by unsaturated fatty of in M. S. Hostetler K.Y. Mitochondrial cardiolipin in diverse of biosynthetic reactions and J. 1993; Scholar). The fatty to be the requirement for the of CL M. lipid and in liver mitochondria by to cardiolipin J. 1990; 265: Scholar). of the fatty composition of CL was shown to the in cardiac mitochondria S. R. M. Cardiolipin in rat heart mitochondria to essential fatty 1990; Scholar, S. R. M. from affect bovine heart cytochrome c Scholar). The activity of cytochrome c reconstituted CL and of the the fatty composition of CL is for mitochondrial activity. CL de novo biosynthesis the of acid to by R.A. H. The biosynthesis of Biol. Chem. Scholar). is to phosphatidylglycerol phosphate by phosphate synthase The phosphate is to by a active phosphate is of to CL by CL synthase K.Y. H. of cardiolipin in rat Acta. Scholar). The de novo CL biosynthetic enzymes fatty B. Schlame M. H. G. D. of and phosphatidylglycerol de novo in rat liver mitochondria.Biochim. Biophys. Acta. 1989; Scholar, K.Y. P. van H. on the formation of cardiolipin and phosphatidylglycerol in rat liver effect of and the fatty acid composition of Biophys. Acta. Scholar). CL be by a pathway to fatty M. B. formation and in rat liver J. 1990; Scholar). The for CL in the mitochondria is J. of in outer membrane of Biophys. Res. Commun. Scholar, I. in 1981; Scholar, P. of the mitochondrial outer membrane and inner Biophys. Res. Commun. Scholar). We the activity of acyltransferase for the of to CL in the heart and mammalian B.J. V. of in rat Lipid Res. Scholar). the of mammalian cells that be toward for reactions P. Coleman R.A. in of J. 2000; Scholar, J. inhibits fatty acid and and in from Scholar, R.A. and of enzymes of 2000; Scholar, into 1,2,3-triacyl-sn-glycerol and and metabolism in Lipid Res. Scholar). Etomoxir is a of the acid carnitine and has been as a for the treatment of heart K. of and carnitine by 1984; Scholar, M. a to treatment of heart 2000; Scholar, S. etomoxir in heart Sci. 2000; Scholar). etomoxir treatment inhibits the activity of carnitine I. a fatty acid into the mitochondria and is fatty acid and is etomoxir diverse effects on the of metabolic enzymes D. G. of etomoxir on the of in and Scholar). been that etomoxir treatment de novo phospholipid biosynthesis in the mammalian heart V. H. of lipid metabolism in heart function and Scholar). been In examined etomoxir treatment of H9c2 cardiac myoblast cells de novo CL and phospholipid and etomoxir mediated distinct metabolic channeling of fatty acid and glycerol into CL. results indicate that etomoxir treatment of H9c2 cardiac myoblast cells a diverse of effects on de novo glycerolipid biosynthesis from various metabolic precursors. In addition, etomoxir a distinct and differential metabolic channeling of glycerol and fatty acid precursors into CL in H9c2 cells. heart H9c2 cells from [1-14C]palmitic [1-14C]oleic and from or was from as G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). was from was as M. J. B. D. J. G. by of rat liver carnitine is produced through the J. 2000; 351: Scholar). and bovine of Lipid from was from layer from was from or and from or heart H9c2 cells in bovine In cells for in the or presence of etomoxir and for [1-14C]oleic acid to in a In cells for or etomoxir and for or [1,3-3H]glycerol [1-14C]oleic acid to in a [1-14C]palmitic acid to in a [3H]serine or myo-[3H]inositol The was and the cells and from the for lipid An of the was for the of uptake of into cells. and in as G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). H9c2 cells and The cells of a The was for The was for The was in of and the mitochondrial The was for to the The from was in of and the kinase in was by the of [1,3-3H]glycerol to as Scholar). Mitochondrial activity was by the of and to as G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). Mitochondrial phosphate synthase and phosphate activities by the of and to as G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). Mitochondrial CL synthase activity was by the of and to as G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). Mitochondrial was by the of to as A. in cardiac phosphatidylglycerol in not affect cardiolipin for distinct of phosphatidylglycerol in the J. Scholar). Mitochondrial activity was by the of and to as B.J. V. of in rat Lipid Res. Scholar). Mitochondrial and acyltransferase activities as D. A. acyltransferase from Scholar). 1,2-diacyl-sn-glycerol acyltransferase activity was as R.A. and acyltransferase from liver and Scholar). and membrane phosphatidate phosphohydrolase activity was as A. A. of acid on the activities of distinct phosphatidate in rat Lett. Scholar). In and glycerol kinase activities in the or presence of The fatty acid composition of CL in H9c2 cells was as P.J. The of in mammalian Scholar). Phospholipid was as G. S. A. thin layer separation of and of by of Scholar). was as the Biol. Chem. and was for The of was as < acid into mitochondria and its is mediated by carnitine and J. acid into mitochondria.Biochim. Biophys. Acta. 2000; Scholar). is a to in mitochondria by carnitine activity K. of and carnitine by 1984; Scholar). was that etomoxir phospholipid biosynthesis in mammalian heart V. H. of lipid metabolism in heart function and Scholar). the effect of etomoxir on the biosynthesis of a phospholipid in not been We H9c2 cardiac myoblast cells it is a derived from rat heart and cells glycerol and fatty and into CL G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Scholar). H9c2 cells etomoxir for and [1-14C]oleic acid to for and into CL of etomoxir been in various to carnitine activity The flux of carnitine on in rat J. Scholar, A. M. R. T. M. in of rat Biophys. Res. Commun. Scholar). acid was for is the major unsaturated fatty acid in CL in H9c2 cells The treatment was to the effects of D. G. of etomoxir on the of in and Scholar). In H9c2 CL was of and of H9c2 cells etomoxir resulted in a reduction in [1-14C]oleic acid incorporation into CL to etomoxir the reduction in [1-14C]oleic acid incorporation into CL was The presence of etomoxir in the of H9c2 cells did not the fatty acid composition of CL We examined incorporation of [1-14C]oleic acid into lipid of the of cells etomoxir caused a (P < 0.05) and (P < 0.05) reduction in [1-14C]oleic acid into CL and In contrast, into was into was not associated the cells was by etomoxir etomoxir treatment [1-14C]oleic acid incorporation into and fatty acid composition of cardiolipin in H9c2 cells cells for in the or presence of Cardiolipin (CL) was and the fatty acid composition of CL the of in a of [1-14C]oleic acid into and CL in H9c2 cells < < cellular cells for in the or presence of [1-14C]oleic acid and the into acid phosphatidylglycerol and CL the of < in a H9c2 cells for in the or presence of Cardiolipin (CL) was and the fatty acid composition of CL the of H9c2 cells for in the or presence of [1-14C]oleic acid and the into acid phosphatidylglycerol and CL the of The mechanism for the reduction in [1-14C]oleic acid incorporation into and CL was The phospholipid of cells was and was by etomoxir for The phospholipid of CL in cells was and was by etomoxir for [1-14C]oleic acid into was examined the reduction in [1-14C]oleic acid into and CL was to a reduction in the activities of the enzymes of the pathway of CL biosynthesis. for in the or presence of The cells mitochondrial and the activities of the biosynthetic enzymes in etomoxir did not affect mitochondrial phosphate or CL synthase the reduction in [1-14C]oleic acid incorporation into and CL was not to in the activities of the enzymes of de novo CL phosphate CL acyltransferase acyltransferase 1,2-diacyl-sn-glycerol acyltransferase phosphatidate phosphohydrolase and glycerol kinase activities in H9c2 cells < < of on < cells for in the of presence of and and phosphate CL and glycerol kinase activities The results the of < in a H9c2 cells for in the of presence of and and phosphate CL and glycerol kinase activities The results the of fatty into by B. and of acid in rat Biophys. Acta. Scholar). [1-14C]oleic acid incorporation into and CL to a and is the to it was that the reduction in into CL was to a a reduction in the of its or a reduction in CL cells etomoxir for [1-14C]palmitic acid for and into In rat acid CL by de novo biosynthesis B.J. V. of in rat Lipid Res. Scholar). in of cells etomoxir caused a (P < 0.05), (P < 0.05), and (P < 0.05) reduction in [1-14C]palmitic acid into and phosphatidylinositol In contrast, into phosphatidylethanolamine phosphatidylcholine and (P < 0.05), (P < 0.05), and (P < 0.05), in cells into was not [1-14C]palmitic acid into was increased (P < 0.05), and incorporation into 1,2,3-triacyl-sn-glycerol (P < 0.05) in cells associated the cells was by etomoxir We examined etomoxir mitochondrial and the CL remodeling H9c2 cells etomoxir for The cells mitochondrial and activities Etomoxir treatment did not affect and activities the reduction in acid incorporation into CL was to the reduction in of its and not to in CL In addition, etomoxir treatment [1-14C]palmitic acid incorporation into and and [1-14C]palmitic acid incorporation into of [1-14C]palmitic acid into and in H9c2 cells < < < < < < < < incorporation into phosphatidylserine. H9c2 cells for in the or presence of etomoxir and [1-14C]palmitic acid and the into 1,2-diacyl-sn-glycerol and 1,2,3-triacyl-sn-glycerol the of < in a phosphatidylserine. H9c2 cells for in the or presence of etomoxir and [1-14C]palmitic acid and the into 1,2-diacyl-sn-glycerol and 1,2,3-triacyl-sn-glycerol the of and de novo biosynthesis and de novo biosynthesis and as precursors. [1-14C]palmitic acid into was and [1-14C]palmitic acid into and it was that etomoxir treatment activity or resulted in a of phospholipid biosynthesis away from reactions toward or etomoxir for and mitochondrial activities and mitochondrial activities in cells etomoxir a in glycerolipid biosynthesis and the of utilization B. and of acid in rat Biophys. Acta. Scholar). or etomoxir for and membrane activity cellular activity was and was by etomoxir treatment of In contrast, membrane was increased 35% (P < 0.05) in cells activity was and was by treatment of treatment of did not affect in activity, it is that the increase in membrane activity in cells etomoxir was caused by the in fatty acid produced by the inhibition of mitochondrial the reduction in fatty acid incorporation into and in cells was to a of glycerolipid biosynthesis away from reactions toward etomoxir [1-14C]palmitic acid incorporation into We examined etomoxir activity. H9c2 cells etomoxir for The cells and and activities activity was 81% (P < 0.05) in cells The mechanism of the inhibition of activity was from H9c2 cells and activity in the or presence of activity was in and was (P < 0.05) to in [1-14C]palmitic acid incorporation into was and activity that the reduction in [1-14C]palmitic acid incorporation into was to a decrease in flux of fatty toward biosynthesis mediated by an inhibition in activity. etomoxir inhibited CL formation from fatty acid in H9c2 that etomoxir CL biosynthesis from the glycerol etomoxir treatment de novo CL biosynthesis from H9c2 cardiac myoblast cells for in the or presence of etomoxir and [1,3-3H]glycerol for and into CL and of the pathway of CL biosynthesis was of cells etomoxir resulted in (P < 0.05), (P < 0.05), and (P < 0.05) increase in [1,3-3H]glycerol incorporation into and into was not uptake of [1,3-3H]glycerol in H9c2 cells was by the presence of the activity of the glycerol been by the glycerol the was [1,3-3H]glycerol in the The of glycerol is of glycerol J. The effects of and glycerol on glycerol uptake in rat liver and J. Scholar). to the results and biosynthesis and uptake of [1,3-3H]glycerol was by etomoxir treatment in etomoxir treatment of H9c2 cells de novo CL biosynthesis from of [1,3-3H]glycerol into in H9c2 cells < < < uptake of < < < < < < < < < uptake of cells for in the or presence of etomoxir and or glycerol and the into the of < in a H9c2 cells for in the or presence of etomoxir and or glycerol and the into the of We examined the mechanism for the increase in glycerol incorporation into CL. glycerol kinase is the step in glycerol metabolism E. of of glycerol kinase on lipid and metabolism in Biol. Chem. examined glycerol kinase activity was in cells. for in the or presence of and and glycerol kinase activity kinase activity was 33% (P < 0.05) in cells The mechanism for the in glycerol kinase activity was from H9c2 cells and glycerol kinase activity was in the or presence of The presence of in the glycerol kinase in activity (P < 0.05) from to the activities of the de novo CL biosynthetic and glycerol uptake the in into CL in etomoxir cells was to an increase in glycerol flux through the pathway mediated by an increase in glycerol kinase activity. [1,3-3H]glycerol incorporation into was increased by etomoxir examined incorporation into was in into and was (P < 0.05), (P < 0.05), (P < 0.05), and (P < 0.05), in cells an in biosynthesis of from which be glycerol kinase activity was In contrast, incorporation of [1,3-3H]glycerol into and was 33% (P < 0.05) and (P < 0.05), activity was in cells to indicate that [1,3-3H]glycerol was toward biosynthesis the of biosynthesis. We examined the effect of etomoxir on the biosynthesis of from de novo H9c2 cells etomoxir for or for incorporation into was increased (P < 0.05) and incorporation into was increased (P < 0.05) in cells etomoxir In addition, incorporation into was increased (P < 0.05) in cells etomoxir uptake of or into H9c2 cells was by etomoxir the presence of etomoxir resulted in a of de novo and biosynthesis by and the increase in biosynthesis from [1-14C]palmitic acid and of into and and incorporation into in < < uptake of uptake of cells for in the or presence of etomoxir and for in the presence of or and the into and The results the of four < in a H9c2 cells for in the or presence of etomoxir and for in the presence of or and the into and The results the of four H9c2 cells etomoxir for myo-[3H]inositol or and the into and of cells etomoxir resulted in a (P < 0.05) decrease in into uptake of inositol was (P < 0.05) in cells which incorporation of myo-[3H]inositol into was uptake of [3H]serine into cells was by of cells etomoxir resulted in a (P < 0.05) decrease in into In contrast, etomoxir treatment resulted in a (P < 0.05) increase in into The reduction in into was for by the in that etomoxir synthesis from etomoxir inhibited de novo biosynthesis and biosynthesis from the results indicate that etomoxir treatment has diverse effects on de novo phospholipid biosynthesis from various metabolic precursors. In addition, etomoxir mediates a distinct and differential metabolic channeling of glycerol and fatty acid precursors into of myo-[3H]inositol into and [3H]serine incorporation into and in < uptake of < < < uptake of cells for in the or presence of and for in the presence of myo-[3H]inositol or and the into and The results the of four < in a H9c2 cells for in the or presence of and for in the presence of myo-[3H]inositol or and the into and The results the of four The of was to etomoxir treatment CL biosynthesis in H9c2 cells and etomoxir mediated metabolic channeling of fatty acid and glycerol precursors into CL. results indicate that etomoxir treatment of H9c2 cardiac myoblast cells a diverse of effects on de novo glycerolipid biosynthesis from various metabolic precursors. In addition, etomoxir a distinct and differential metabolic channeling of glycerol and fatty acid precursors into CL in H9c2 cardiac myoblast cells. The of de novo CL biosynthesis been shown to on the inner side of the inner mitochondrial membrane M. D. Cardiolipin is on the side of the inner membrane in rat liver mitochondria.J. Biol. Chem. 1993; Scholar). Etomoxir is by cells and to a of mitochondrial fatty acid and The is an of fatty acid and an in of H9c2 cells etomoxir the incorporation of into CL and in H9c2 cardiac myoblast cells but did not affect incorporation of into cells. In addition, the activities of the enzymes of the pathway of CL biosynthesis by etomoxir results that the reduction in fatty acid incorporation into CL was not to a reduction in acid uptake or a decrease in the de novo CL biosynthetic In contrast, incorporation of acid into and in cells. fatty acid incorporation into was by etomoxir results that etomoxir treatment mediated a redirection of phospholipid biosynthesis from fatty acid precursors away from and toward that be of fatty for various glycerolipid biosynthetic P. Coleman R.A. in of J. 2000; Scholar, J. inhibits fatty acid and and in from Scholar, R.A. and of enzymes of 2000; Scholar, into 1,2,3-triacyl-sn-glycerol and and metabolism in Lipid Res. Scholar). In the the redirection in fatty for lipid synthesis was mediated by an increase in membrane activity in cells. in activity was in of cells etomoxir an in fatty and increase in fatty acid membrane activity in D. lipid phosphatidate Biol. Chem. Scholar). the mechanism for the reduction in fatty acid incorporation into and CL to be a decrease in fatty acid flux through the Etomoxir treatment of H9c2 cells resulted in an in the [1-14C]palmitic for and biosynthesis. The in and biosynthesis from [1-14C]palmitic acid was in the and In and de novo biosynthesis by and by The increase in [1-14C]palmitic acid into in the presence of etomoxir was to an increase in the of its and phospholipid synthesis by inhibition of mitochondrial been V. H. of lipid metabolism in heart function and but the not been that of etomoxir synthesis Y. M. M. T. of carnitine synthesis and Biol. Chem. Scholar). We incorporation into in H9c2 cells etomoxir an in etomoxir treatment [1-14C]palmitic acid incorporation into activity was in cells and inhibited in activity. that the reduction in fatty acid incorporation into was to a channeling of for synthesis synthesis and the of of of fatty for various glycerolipid biosynthetic Coleman R.A. and in in rat liver and be inhibited Biol. Chem. Scholar). The de novo enzymes for CL biosynthesis B. Schlame M. H. G. D. of and phosphatidylglycerol de novo in rat liver mitochondria.Biochim. Biophys. Acta. 1989; Scholar, K.Y. P. van H. on the formation of cardiolipin and phosphatidylglycerol in rat liver effect of and the fatty acid composition of Biophys. Acta. and activity be for the remodeling of CL T. B.J. of activity in rat J. 2000; Scholar). it was that the reduction in [1-14C]oleic acid incorporation into CL was to a of fatty acid for CL remodeling or to in the activity of the CL remodeling acid into rat heart CL by the de novo biosynthetic pathway B.J. V. of in rat Lipid Res. Scholar). a reduction in incorporation into CL was both [1-14C]palmitic acid and [1-14C]oleic and the activities of the CL remodeling enzymes in mitochondrial in it be that the reduction in acid incorporation into CL was not to a of fatty acid for CL In of was the that the reduction in acid incorporation into the of was to that of CL in cells. In addition, mitochondrial activity was by etomoxir on the of synthesis in rat liver mitochondria that and from and on the outer of the mitochondrial outer membrane and that is by of to the inner membrane for and CL biosynthesis A. D. acid synthesis in of formation and Biol. Chem. Scholar). We to a reduction in [1,3-3H]glycerol incorporation into CL in cells etomoxir acid incorporation into CL was and the activities of the enzymes of the pathway of CL biosynthesis the was of cells etomoxir resulted in an increase in [1,3-3H]glycerol incorporation into CL and [1,3-3H]glycerol incorporation into cells was that etomoxir treatment mediated metabolic channeling of glycerol into CL and glycerol kinase as a step in glycerol metabolism E. of of glycerol kinase on lipid and metabolism in Biol. Chem. Scholar). We an increase in glycerol kinase activity in cells and glycerol kinase in activity. The increase in glycerol kinase activity in cells the in [1,3-3H]glycerol incorporation into CL and activities [1,3-3H]glycerol incorporation into was by channeling of glycerol away from biosynthesis. The reduction in activity in cells was for the reduction in synthesis from [1,3-3H]glycerol incorporation into was in cells. indicate the of of for glycerolipid synthesis in H9c2 a that be for synthesis and a for glycerolipid etomoxir did not affect de novo phospholipid biosynthesis from precursors in an de novo biosynthesis from was inhibited in H9c2 cells in the presence of The mechanism was an reduction in uptake of of was in H9c2 cells and biosynthesis from was it that biosynthesis from was in cells. is from by in the mitochondria of from or to mitochondria. by a Biophys. Acta. Scholar). the of into both and was in both and it be that biosynthesis was by etomoxir treatment and that to was increased by etomoxir The in de novo phospholipid biosynthesis effects in of D. G. of etomoxir on the of in and Scholar, The flux of carnitine on in rat J. Scholar, A. M. R. T. M. in of rat Biophys. Res. Commun. Scholar). In of was the that CL fatty acid composition and by of H9c2 cells that etomoxir did not the fatty acid of in and rat J. J.N. W.B. Phospholipid fatty acid composition in and rat Scholar). In 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. was by a from the of to acyltransferase 1,2-diacyl-sn-glycerol cardiolipin 1,2-diacyl-sn-glycerol 1,2-diacyl-sn-glycerol acyltransferase acyltransferase phosphatidate phosphohydrolase phosphatidylcholine phosphatidylethanolamine phosphatidylglycerol phosphatidylinositol acid 1,2,3-triacyl-sn-glycerol

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