Stimulation of cardiac cardiolipin biosynthesis by PPARα activation

The role of peroxisome proliferator-activated receptor α (PPARα)-stimulated phospholipase A2 (PLA2) in cardiac mitochondrial cardiolipin (CL) biosynthesis was examined in both in vivo and in vitro models. Treatment of rat heart H9c2 cells with clofibrate increased the expression and activity of 14 kDa PLA2 but did not affect the pool size of CL. Clofibrate treatment stimulated de novo CL biosynthesis via an increase in phosphatidylglycerolphosphate (PGP) synthase activity, accounting for the unaltered CL content. Cardiac PLA2, PGP synthase, and CDP-1,2-diacyl-sn-glycerol synthase (CDS-2) activities and CDS-2 mRNA levels were elevated in mice fed clofibrate for 14 days compared with controls. In PPARα-null mice, clofibrate feeding did not alter cardiac PLA2, PGP synthase activities, or CDS-2 activity and mRNA level, confirming that these enzymes are regulated by PPARα activation. In contrast to mouse heart, clofibrate treatment did not affect the activity or mRNA levels of CDS-2 in H9c2 cells, indicating that CDS-2 is regulated differently in rat heart H9c2 cells in vitro and in mouse heart in vivo.These results clearly indicate that cardiac CL de novo biosynthesis is stimulated by PPARα activation in responsive rodent models and that CDS-2 is an example of an enzyme that exhibits alternative regulation in vivo and in cultured cell lines. This study is the first to demonstrate that CL de novo biosynthesis is regulated by PPARα activation. The role of peroxisome proliferator-activated receptor α (PPARα)-stimulated phospholipase A2 (PLA2) in cardiac mitochondrial cardiolipin (CL) biosynthesis was examined in both in vivo and in vitro models. Treatment of rat heart H9c2 cells with clofibrate increased the expression and activity of 14 kDa PLA2 but did not affect the pool size of CL. Clofibrate treatment stimulated de novo CL biosynthesis via an increase in phosphatidylglycerolphosphate (PGP) synthase activity, accounting for the unaltered CL content. Cardiac PLA2, PGP synthase, and CDP-1,2-diacyl-sn-glycerol synthase (CDS-2) activities and CDS-2 mRNA levels were elevated in mice fed clofibrate for 14 days compared with controls. In PPARα-null mice, clofibrate feeding did not alter cardiac PLA2, PGP synthase activities, or CDS-2 activity and mRNA level, confirming that these enzymes are regulated by PPARα activation. In contrast to mouse heart, clofibrate treatment did not affect the activity or mRNA levels of CDS-2 in H9c2 cells, indicating that CDS-2 is regulated differently in rat heart H9c2 cells in vitro and in mouse heart in vivo. These results clearly indicate that cardiac CL de novo biosynthesis is stimulated by PPARα activation in responsive rodent models and that CDS-2 is an example of an enzyme that exhibits alternative regulation in vivo and in cultured cell lines. This study is the first to demonstrate that CL de novo biosynthesis is regulated by PPARα activation. Phospholipids are important structural and functional components of the biological membrane (1White D.A. The phospholipid composition of mammalian tissues.in: Ansell G.B. Hawthorne J.N. Dawson R.M.C. Form and Function of Phospholipids. Elsevier Science Publishers, Amsterdam1973: 441-483Google Scholar). Structurally, as major components of the biological membrane, they define the compartmentalization of organelles and the protective barrier, the cell membrane, that surrounds cells. An important class of phospholipids are the polyglycerophospholipids. The major polyglycerophospholipid found in most mammalian tissues is bis-(1,2-diacyl-sn-glycero-3-phospho)-1′,3′-sn-glycerol or cardiolipin (CL) (2Hostetler K.Y. Polyglycerophospholipids.in: Hawthorne J.N. Ansell G.B. Phospholipids. Elsevier Science Publishers, Amsterdam1982: 215-261Google Scholar). CL was first isolated from beef heart in 1942 by Pangborn (3Pangborn M.C. Isolation and purification of a serologically active phospholipid from beef heart.J. Biol. Chem. 1942; 143: 247-256Abstract Full Text PDF Google Scholar). In rat liver, CL was initially shown to be associated exclusively with the inner mitochondrial membrane (4Stoffel W. Schiefer H-G. Biosynthesis and composition of phosphatides in outer and inner mitochondrial membranes.Hoppe-Seyler's Z. Physiol. Chem. 1968; 349: 1017-1026Crossref PubMed Scopus (103) Google Scholar). However, using various fractionation techniques, CL was identified also in the mitochondrial outer membrane of rat liver mitochondria (5Hovius R. Lambrechts H. Nicolay K. de Kruijff B. Improved methods to isolate and subfractionate rat liver mitochondria. Lipid composition of the inner and outer membrane.Biochim. Biophys. Acta. 1990; 1021: 217-226Crossref PubMed Scopus (311) Google Scholar). In rat heart, CL is a major phospholipid component that constitutes ∼15% of the entire phospholipid phosphorus mass of the organ (6Poorthuis B.J.H.M. Yazaki P.J. Hostetler K.Y. An improved two-dimensional thin layer chromatography system for the separation of phosphatidylglycerol and its derivatives.J. Lipid Res. 1976; 17: 433-437Abstract Full Text PDF PubMed Google Scholar, 7Hatch G.M. Cardiolipin biosynthesis in the isolated heart.Biochem. J. 1994; 297: 201-208Crossref PubMed Scopus (66) Google Scholar). CL is involved in modulation of the activity of a number of mitochondrial membrane enzymes involved in the generation of ATP (8Hoch F.L. Cardiolipins and biomembrane function.Biochim. Biophys. Acta. 1992; 1113: 71-133Crossref PubMed Scopus (546) Google Scholar). It is well documented that alteration in the content and the molecular species composition of CL alters mitochondrial enzyme activity and oxygen consumption in mammalian mitochondria (9Yamaoka-Koseki S. Urade R. Kito M. Cardiolipins from rats fed different dietary lipids affect bovine heart cytochrome c oxidase activity.J. Nutr. 1991; 121: 956-958Crossref PubMed Scopus (42) Google Scholar, 10Ohtsuka T. Nishijima M. Suzuki K. Akamatsu Y. Mitochondrial dysfunction of a cultured Chinese hamster ovary cell mutant defective in cardiolipin.J. Biol. Chem. 1993; 268: 22914-22919Abstract Full Text PDF PubMed Google Scholar). Recently, CL has been implicated as an important mitochondrial factor that may be involved in the regulation of apoptosis (11Esposti M.D. Lipids, cardiolipin and apoptosis: a greasy license to kill.Cell Death Differ. 2002; 9: 234-236Crossref PubMed Scopus (61) Google Scholar, 12McMillann Dowhan W. Cardiolipin and apoptosis.Biochim. Biophys. Acta. 2002; 1585: 97-107Crossref PubMed Scopus (239) Google Scholar). Thus, maintenance of the appropriate content of CL in cardiac mitochondria is essential for proper cardiac function. The de novo biosynthesis of CL in the rat heart occurs via the CDP-1,2-diacyl-sn-glycerol (CDP-DG) pathway (2Hostetler K.Y. Polyglycerophospholipids.in: Hawthorne J.N. Ansell G.B. Phospholipids. Elsevier Science Publishers, Amsterdam1982: 215-261Google Scholar). Phosphatidic acid (PA) is converted to CDP-DG by CDP-DG synthase (CDS; EC 2.2.7.41) (13Kiyasu J.Y. Pieringer R.A. Paulus H. Kennedy E.P. The biosynthesis of phosphatidylglycerol.J. Biol. Chem. 1963; 238: 2293-2298Abstract Full Text PDF PubMed Google Scholar). In the rat heart and in embryonic rat heart-derived H9c2 myoblast cells, CDS may be a rate-limiting enzyme for CL biosynthesis (7Hatch G.M. Cardiolipin biosynthesis in the isolated heart.Biochem. J. 1994; 297: 201-208Crossref PubMed Scopus (66) Google Scholar, 14Hatch G.M. McClarty G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The CDP-DG with to phosphatidylglycerol by (PGP) synthase and PGP (13Kiyasu J.Y. Pieringer R.A. Paulus H. Kennedy E.P. The biosynthesis of phosphatidylglycerol.J. Biol. Chem. 1963; 238: 2293-2298Abstract Full Text PDF PubMed Google Scholar). In the is converted to CL by with CDP-DG by CL synthase K.Y. H. Biosynthesis of cardiolipin in rat liver Biophys. Acta. PubMed Scopus Google Scholar). CL may be by mitochondrial phospholipase A2 (PLA2) (2Hostetler K.Y. Polyglycerophospholipids.in: Hawthorne J.N. Ansell G.B. Phospholipids. Elsevier Science Publishers, Amsterdam1982: 215-261Google Scholar). that mitochondrial PLA2 in rat embryonic H9c2 cells be by or G.M. phosphatidylglycerolphosphate synthase activity in H9c2 cardiac J. PubMed Scopus Google Scholar). This activation of mitochondrial PLA2 to an increase in CL biosynthesis that was by of mitochondrial PGP synthase proliferator-activated are that to the receptor M. W. expression of peroxisome proliferator-activated of and in the PubMed Scopus Google Scholar, proliferator-activated in the J. PubMed Scopus Google Scholar, B. J. of expression by Full Text Full Text PDF PubMed Scopus Google Scholar). been and It is well documented that the rat heart is a in The of clofibrate in rodent heart is by PPARα with the receptor and with in the of study that the mRNA of was elevated in and embryonic rat heart-derived H9c2 myoblast cells, PPARα activation M. of expression in the rat J. PubMed Scopus Google Scholar). However, the of PPARα in H9c2 cells was not examined in that PPARα activation PLA2 activity K. J. M. of phospholipase A2 expression by peroxisome proliferator-activated receptor in rat 2002; PubMed Google Scholar, G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google the role of receptor in CL biosynthesis was examined in embryonic rat heart H9c2 cells and mouse The results that activation of PPARα increased CL biosynthesis and via an increase in mitochondrial PLA2 and PGP synthase However, activation of a rate-limiting enzyme of CL biosynthesis in rat heart embryonic H9c2 cells, is not for the PPARα of de novo CL and were from or was from G.M. McClarty G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and were of Lipid were from were from was from heart H9c2 cells were from the PPARα and were from was from were from was a from J. for The system was for PPARα and PLA2 expression and was from was from were or and from or mice were from of PPARα-null mice were a from of Treatment of mice to the of the The mice were rat and were in a of of and of In treatment mice were fed clofibrate in a for 14 days D.A. M. the peroxisome proliferator-activated receptor as the for acid of Lipid Res. Full Text Full Text PDF PubMed Google Scholar). heart H9c2 cells were and in was were for with in the or of clofibrate or The was In cells were with for to with The was and the cells were with and from the with of for CL was from phospholipids by two-dimensional and CL and phospholipids was as G.M. McClarty G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In H9c2 cells were with for and in the or of clofibrate for to and the CL was H9c2 cells were for with in the or of The was the cells were with and with of and The cells were with of a The the cell was for and the was for The was in of and the mitochondrial PGP synthase, and CL synthase activities were as G.M. McClarty G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In clofibrate was to the enzyme of mitochondrial from H9c2 cells, and PGP synthase, and CL synthase activities were PLA2 activity was as G.M. in cardiac phosphatidylglycerol in for of phosphatidylglycerol in the heart.Biochem. J. PubMed Scopus Google Scholar). activity also was as G.M. of acid and cardiolipin in H9c2 Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). H9c2 cells were for with in the or of The was The cells were and and mitochondrial were as of the or mitochondrial was to with molecular using a were from the by for using a of PPARα was examined by the membrane with the PPARα in and the membrane was and with for in the membrane were by of 14 kDa PLA2, to the were with The membrane was and with the for The of the were by the and using G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). were to of H9c2 cells were the for were for with in the or of clofibrate The was The was and the cells were with for and using and for The cells were with and in with of and and be for to The cells were with and for were and of the and in a The was cell in that were with of the was and with were of the and in the for in a The were as with of the cells was with in were with and with were with and cell with of to were using an with and to and for the of and The for CDS-2 was with a of by The rat CDS-2 for the were M. M. S. B. and of a mammalian of the PubMed Scopus Google CDS-2 and CDS-2 H9c2 cells were for to with and was isolated using the to the The was in and by using the as an of The of the was by of the isolated The from of was using of of of and of the in a of The was for and by the for An of the was for was in of of and of The was with of to and was in a the the of of for for and for The was by in and and by with The was as an An increase in the of a mRNA is by an increase in its of a in its of or a of these mRNA were using as an of H9c2 cells were with clofibrate for and was clofibrate The mRNA levels for CDS-2 and were by the in mRNA were a indicating that clofibrate did not in the of CDS-2 the for rat a for and was for of CDS-2 in mouse heart for were and The for were of for for and for The was as was by the of with the Biol. Chem. Full Text PDF PubMed Google Scholar). was to The of was as activation of mitochondrial PLA2 by or in the of CL biosynthesis in rat heart H9c2 cardiac myoblast cells G.M. phosphatidylglycerolphosphate synthase activity in H9c2 cardiac J. PubMed Scopus Google Scholar). that PPARα activation in an increase in PLA2 activity in cells and in rat cells K. J. M. of phospholipase A2 expression by peroxisome proliferator-activated receptor in rat 2002; PubMed Google Scholar, G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). the heart examined activation of PLA2 a and stimulated CL examined the expression of PPARα in H9c2 cells with PPARα H9c2 cells were to and and were PPARα receptor was in the of H9c2 cells PPARα activation in rat cells by in increased of PPARα in the of responsive and species PubMed Scopus Google Scholar). examined the to H9c2 cells of a of in increased of H9c2 cells were for to with clofibrate and and were that of clofibrate was shown to in PPARα activation in G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). of H9c2 cells with clofibrate in a increase in PPARα compared with cells It is that clofibrate may be to cells in that of of H9c2 cells with clofibrate did not affect the of these cells to Thus, H9c2 cells and clofibrate to H9c2 cells in the activation of the activation of PPARα in H9c2 cells increased PLA2 activity, cells were in the or of clofibrate for and and PLA2 activity was in treatment of H9c2 cells with clofibrate in a increase in membrane PLA2 activity compared with cells. examined the for the increase in PLA2 that the expression of PLA2 activity and expression were by PPARα in cells G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). H9c2 cells were for with and the of PLA2 was examined by Clofibrate of H9c2 cells in an increase in PLA2 that was by the of of the of cell Thus, PPARα activation by clofibrate in an increase in the expression of However, PLA2 not to CL in mitochondria J. T. J. phospholipase A2 with membrane, and membrane in J. PubMed Scopus Google examined 14 kDa PLA2 activity and expression in mitochondria. H9c2 cells were for with clofibrate and mitochondrial were PLA2 activity was and the of 14 kDa PLA2 was examined by of H9c2 cells with clofibrate in a increase in mitochondrial PLA2 activity and a increase in 14 kDa PLA2 associated with cell and mitochondrial compared with The 14 kDa PLA2 was not in indicating that was of the enzyme to the fractionation Thus, PPARα activation by clofibrate in in mitochondrial 14 kDa PLA2 enzyme activity and expression in H9c2 activities in H9c2 cells with cells were in the or of clofibrate for The cells were and enzyme activities were in the cell and in mitochondrial of PLA2, phospholipase in a of 14 kDa PLA2 in rat heart H9c2 cells with H9c2 cells were in the or of clofibrate for The cells were and mitochondrial were PLA2 was in and mitochondrial using and the of the were using cells. mitochondria from mitochondria from from from cells. are H9c2 cells were in the or of clofibrate for The cells were and enzyme activities were in the cell and in mitochondrial of PLA2, phospholipase mitochondrial PLA2 activity was elevated in H9c2 cells with examined the pool size of CL was in these cells. The CL pool size was in H9c2 cells of and was unaltered by clofibrate treatment examined the of CL in cells with clofibrate using a H9c2 cells were for with the was the cells were in the or of clofibrate for to and the CL was CL of with was associated with CL was the in cells but was a in cells with Thus, the of clofibrate in an increase in CL in H9c2 cells. the pool size of CL was unaltered mitochondrial PLA2 and CL were increased by clofibrate was that CL biosynthesis was increased in cells to the CL pool H9c2 cells were with clofibrate or PPARα for by with for and phospholipids was that of in PPARα activation in G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). CL was increased by in cells and by in cells compared with In the phospholipid of was increased by in cells and by in cells compared with controls. of H9c2 cells was and was unaltered by clofibrate or Thus, the increase in and CL in or cells was not to an increase in the of H9c2 of CL and in H9c2 cells with clofibrate or of cells were in the or of clofibrate or for by with for Cardiolipin (CL) and phosphatidylglycerol were isolated by and the these was of in a H9c2 cells were in the or of clofibrate or for by with for Cardiolipin (CL) and phosphatidylglycerol were isolated by and the these was of The for the increase in the of CL was by of the enzymes of the CDP-DG pathway in mitochondrial from and cells. H9c2 cells were for with the cells were isolated and and mitochondrial were PGP synthase, and CL synthase activities were in these mitochondrial Treatment of cells with clofibrate in a increase in the activity of PGP synthase In CDS and CL synthase activities were unaltered compared with of controls. shown G.M. of acid and cardiolipin in H9c2 Lipid Res. Full Text Full Text PDF PubMed Scopus Google of activity was to of H9c2 cells, and treatment with clofibrate did not alter the of activity associated with not the of clofibrate to the of mitochondrial from H9c2 cells was PGP synthase, and CL synthase activities were and and were unaltered by the of clofibrate in the PGP synthase, and CL synthase activities in H9c2 cells with synthase cells were in the or of clofibrate for Mitochondrial were and mitochondrial CDP-1,2-diacyl-sn-glycerol synthase phosphatidylglycerolphosphate (PGP) synthase, and CL synthase activities were of in a H9c2 cells were in the or of clofibrate for Mitochondrial were and mitochondrial CDP-1,2-diacyl-sn-glycerol synthase phosphatidylglycerolphosphate (PGP) synthase, and CL synthase activities were of the PPARα of cardiac CL cardiac CL was examined in rodent were fed clofibrate for 14 the were and the activities of the mitochondrial CL enzymes and PLA2 activity were in clofibrate treatment of mice in a and a increase in cardiac PLA2 and PGP synthase activities, compared with of CL synthase activity was unaltered by clofibrate In contrast to H9c2 cells, CDS activity was increased by in mice compared with These to indicate that CDS activity is regulated differently by clofibrate in these different rodent models. and to that PLA2 and PGP synthase activities are regulated by PPARα the activities of these enzymes were examined in PPARα-null mice with PLA2, PGP synthase, and CL synthase activities were unaltered in PPARα-null mice compared with controls. Thus, cardiac mitochondrial PLA2, PGP synthase, and CDS activities are regulated by PPARα activation in mouse PGP synthase, CL synthase, and PLA2 activities in and PPARα-null mice with were fed clofibrate for 14 cardiac mitochondrial were and mitochondrial PGP synthase, CL synthase, and PLA2 activities were of in a were fed clofibrate for 14 cardiac mitochondrial were and mitochondrial PGP synthase, CL synthase, and PLA2 activities were of mRNA is not in mammalian heart S. The role of synthase and synthase activity levels in the regulation of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, examined the expression of CDS-2 in H9c2 cells with The of for both rat and mouse CDS-2 is in in the expression of CDS-2 mRNA in H9c2 cells was unaltered by with clofibrate for to Thus, CDS-2 is not PPARα activation in H9c2 cells. examined CDS-2 mRNA expression in of and PPARα-null in the expression of cardiac CDS-2 mRNA was increased by in but not in PPARα-null mice with of clofibrate CDS-2 mRNA levels in H9c2 cells. H9c2 cells were for to with and mRNA levels were by as in and are of clofibrate CDS-2 mRNA levels in and PPARα-null and PPARα-null mice were fed a or a clofibrate for 14 days from The were and mRNA levels were by as in and The the from The of the were using The for the from were for mice mice and for PPARα-null mice PPARα-null mice fed clofibrate of that CL de novo biosynthesis is regulated by PPARα activation in both mouse heart and rat heart embryonic H9c2 cells. However, CDS activity and mRNA expression were to PPARα activation in rat heart H9c2 cells but cardiac CDS activity and mRNA expression were increased in mice with that enzyme may be regulated in different rodent models. The of study was to CL biosynthesis was regulated by The results indicate the rat heart H9c2 cells clofibrate treatment of H9c2 cells the of clofibrate of PPARα in H9c2 cells results in an increase in mitochondrial PLA2 and CL de novo the for the increase in CL biosynthesis in H9c2 cells is an increase in PGP synthase and CDS-2 is a PPARα in mouse heart but not in rat heart H9c2 cells. The and are a class of that levels of and in and rodent species M. W. expression of peroxisome proliferator-activated of and in the PubMed Scopus Google Scholar, proliferator-activated in the J. PubMed Scopus Google Scholar, B. J. of expression by Full Text Full Text PDF PubMed Scopus Google Scholar, peroxisome in and its to Chem. 1993; PubMed Scopus Google Scholar, J. B. J. W. peroxisome a to Scopus Google Scholar, D.A. of peroxisome proliferator-activated in Scholar). These by to PPARα and the expression of the of PPARα in rat heart H9c2 cells. of and rat cells with clofibrate results in the activation of and enzyme activities, K. J. M. of phospholipase A2 expression by peroxisome proliferator-activated receptor in rat 2002; PubMed Google Scholar, G.M. T. of phospholipase A2 by in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). Treatment of H9c2 cells with clofibrate in an increase of both and the expression and activity of 14 kDa in mitochondrial However, the pool size of CL that activation of mitochondrial PLA2 by or a increase in de novo CL biosynthesis via the activation of PGP synthase activity to the CL pool G.M. phosphatidylglycerolphosphate synthase activity in H9c2 cardiac J. PubMed Scopus Google Scholar). Thus, 14 kDa is identified as a PPARα in H9c2 cells. of H9c2 cells with clofibrate in an increase in CL and its phospholipid or are to activity, a of from and Thus, of cells with these affect various Clofibrate the of or activities in rat liver M. the of and phospholipids in rat The of and of J. PubMed Scopus Google Scholar). In with these activity in rat H9c2 cells was unaltered by clofibrate Thus, the increase in and CL was to a the enzymes of the CL of rat heart H9c2 cells with clofibrate in an increase in PGP synthase activity that the increase in CL biosynthesis from in these cells. CDS may be a rate-limiting enzyme of CL biosynthesis in the rat heart and in rat embryonic heart H9c2 cells (7Hatch G.M. Cardiolipin biosynthesis in the isolated heart.Biochem. J. 1994; 297: 201-208Crossref PubMed Scopus (66) Google Scholar, 14Hatch G.M. McClarty G. of cardiolipin biosynthesis in H9c2 cardiac myoblast cells by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). are of the and and is not in mammalian heart S. The role of synthase and synthase activity levels in the regulation of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). treatment of H9c2 cells with clofibrate did not affect CDS enzyme In clofibrate to H9c2 cell mitochondrial did not affect CDS activity not clofibrate treatment did not affect CDS-2 mRNA levels in H9c2 cells. These clearly indicate that CDS-2 is not a PPARα in rat heart H9c2 cells. In contrast to rat H9c2 cells, CDS activity was increased by in cardiac mitochondrial from mice with clofibrate but was unaltered PPARα-null mice were with In CDS mRNA was increased by in from mice with clofibrate but was unaltered PPARα-null mice were with These clearly indicate that CDS is a PPARα in mouse heart but not in rat heart H9c2 cells. clofibrate treatment stimulated cardiac mitochondrial PLA2 and PGP synthase activities in These enzyme activities were unaltered in PPARα-null mice with indicating that they are responsive to PPARα using different rodent the clearly indicate that de novo CL biosynthesis is regulated by It is not these are or regulated by is the of increased mitochondrial CL biosynthesis clofibrate treatment of rat H9c2 cells and mouse and rats are responsive to the biological of peroxisome in and its to Chem. 1993; PubMed Scopus Google Scholar, J. B. J. W. peroxisome a to Scopus Google Scholar). In is to indicate that and are responsive to the of these to be of the for and of by the H. J. H. B. is the for and of Lipid Res. Full Text PDF PubMed Google Scholar). feeding increased rat liver mitochondrial and was associated with a in and In the rat heart, increased CL biosynthesis and were associated with increased mitochondrial G. The of the of in rat heart Biophys. Acta. PubMed Scopus Google Scholar, G.M. phosphatidylglycerolphosphate synthase activity in rat heart Biophys. Acta. PubMed Scopus Google Scholar, T. G.M. regulation of activity in rat heart.Biochem. J. PubMed Google Scholar). Thus, the increase in CL biosynthesis and in H9c2 cells and mouse heart may be to increased mitochondrial for in these the increase in CL biosynthesis may be a by the cell to the CL pool CL is by that the of the factor to H9c2 cells in the activation of mitochondrial PLA2 activity and increased CL in in the activation of PGP synthase and increased CL biosynthesis from G.M. phosphatidylglycerolphosphate synthase activity in H9c2 cardiac J. PubMed Scopus Google Scholar). the of CL (11Esposti M.D. Lipids, cardiolipin and apoptosis: a greasy license to kill.Cell Death Differ. 2002; 9: 234-236Crossref PubMed Scopus (61) Google Scholar, 12McMillann Dowhan W. Cardiolipin and apoptosis.Biochim. Biophys. Acta. 2002; 1585: 97-107Crossref PubMed Scopus (239) Google and the of its M.D. Y. to a molecular mitochondrial and cell Death Differ. PubMed Scopus Google in is that CL is in to CL to and a increased CL biosynthesis may be a protective In rat heart H9c2 cells and its activation results in an increase in de novo CL In PGP synthase and PLA2 were identified as PPARα enzymes involved in the regulation of CL biosynthesis in the mouse CDS-2 was identified as a PPARα and to be regulated by PPARα activation rat cardiac H9c2 cells and mouse heart models. This was by from the and of and of CDP-1,2-diacyl-sn-glycerol CDP-DG synthase cardiolipin acid phosphatidylglycerol phosphatidylglycerolphosphate phospholipase A2 peroxisome proliferator-activated receptor α

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