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Journal of Lipid Research, Vol. 45, 244-252, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Stimulation of cardiac cardiolipin biosynthesis by PPAR activation

Yan J. Jiang^*, Biao Lu^*, Fred Y. Xu, Jennifer Gartshore, William A. Taylor, Andrew J. Halayko, Frank J. Gonzalez^**, Jun Takasaki, Patrick C. Choy^* and Grant M. Hatch^1,*,

^* Center for Research and Treatment of Atherosclerosis and Departments of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
^** National Cancer Institute, National Institutes of Health, Bethesda, MD
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan

¹ To whom correspondence should be addressed. e-mail: hatchgm{at}ms.umanitoba.ca

The role of peroxisome proliferator-activated receptor (PPAR)-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 PPAR-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 PPAR 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 PPAR 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 PPAR activation.

Abbreviations: CDP-DG, CDP-1,2-diacyl-sn-glycerol; CDS, CDP-DG synthase; CL, cardiolipin; PA, phosphatidic acid; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate; PLA₂, phospholipase A₂; PPAR, peroxisome proliferator-activated receptor

Supplementary key words phospholipid • heart • lipid metabolism • gene expression • gene regulation

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