Stimulation of cardiac cardiolipin biosynthesis by PPARalpha activation.
The role of peroxisome proliferator-activated receptor alpha (PPARalpha)-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 PPARalpha-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 PPARalpha 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 PPARalpha 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 PPARalpha activation.
Center for Research and Treatment of Atherosclerosis and Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Yan J
YJ
Jiang
Biao
B
Lu
Fred Y
FY
Xu
Jennifer
J
Gartshore
William A
WA
Taylor
Andrew J
AJ
Halayko
Frank J
FJ
Gonzalez
Jun
J
Takasaki
Patrick C
PC
Choy
Grant M
GM
Hatch
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002308:Cardiolipins / Q000096:biosynthesis*; D002460:Cell Line; D002994:Clofibrate / Q000494:pharmacology; D002798:Diacylglycerol Cholinephosphotransferase / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups)
D000924:Anticholesteremic Agents; D002308:Cardiolipins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D017855:Transferases (Other Substituted Phosphate Groups); D002798:Diacylglycerol Cholinephosphotransferase; C020676:CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase; D010741:Phospholipases A; D054467:Phospholipases A2; D002994:Clofibrate