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Papers In Press, published online ahead of print January 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700184-JLR200

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Journal of Lipid Research, Vol. 49, 84-97, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Myoung Sook Han^1,*, Sun Young Park^1,*, Koei Shinzawa, Sunshin Kim^*, Kun Wook Chung^*, Ji-Hyun Lee, Choon Hyuck Kwon^**, Kwang-Woong Lee^**, Joon-Hyoek Lee^*, Cheol Keun Park, Woo Jin Chung, Jae Seok Hwang, Ji-Jing Yan^***, Dong-Keun Song^***, Yoshihide Tsujimoto and Myung-Shik Lee^2,*

^* Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
^** Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School and Solution Oriented Research for Science and Technology (SORST) of the Japan Science and Technology Corporation, Osaka 565-1871, Japan
Samsung Biomedical Research Institute, Seoul 135-710, Korea
Department of Medicine, Keimyung University School of Medicine, Daegu 700-712, Korea
^*** Department of Pharmacology, College of Medicine, Hallym University, Chunchon, Gangwon 200-702, Korea

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three figures.

Published, JLR Papers in Press, October 18, 2007.

¹ M. S. Han and S. Y. Park contributed equally to this work.

² To whom correspondence should be addressed. e-mail: mslee{at}smc.samsung.co.kr

The pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH using lipoapoptosis models. Palmitic acid (PA) induced classical apoptosis of hepatocytes. PA-induced lipoapoptosis was inhibited by acyl-CoA synthetase inhibitor but not by ceramide synthesis inhibitors, suggesting that conversion products other than ceramide are involved. Phospholipase A₂ (PLA₂) inhibitors blocked PA-induced hepatocyte death, suggesting an important role for PLA₂ and its product lysophosphatidylcholine (LPC). Small interfering RNA for Ca²⁺-independent phospholipase A₂ (iPLA₂) inhibited the lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA₂ inhibitors. Pertussis toxin or dominant-negative G_i mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/G_i. PA decreased cardiolipin content and induced mitochondrial potential loss and cytochrome c translocation. Oleic acid inhibited PA-induced hepatocyte death by diverting PA to triglyceride and decreasing LPC content, suggesting that FFAs lead to steatosis or lipoapoptosis according to the abundance of saturated/unsaturated FFAs. LPC administration induced hepatitis in vivo. LPC content was increased in the liver specimens from NASH patients. These results demonstrate that LPC is a death effector in the lipoapoptosis of hepatocytes and suggest potential therapeutic values of PLA₂ inhibitors or GPCR/G_i inhibitors in NASH.

Supplementary key words fatty acids • phospholipase A₂ • steatohepatitis • triglyceride • ceramide

Abbreviations: A₆₃₀, absorption at 630 nm; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BEL, bromoenol lactone; cPLA₂, cytoplasmic phospholipase A₂; DAG, diacylglycerol; GPCR, G-protein-coupled receptor; iPLA₂, Ca²⁺-independent phospholipase A₂; JNK, c-Jun N-terminal kinase; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPG, lysophosphatidylglycerol; LPI, lysophosphatidylinositol; LPS, lysophosphatidylserine; MAFP, methyl arachidonyl fluorophosphonate; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NAFLD, nonalcoholic fatty liver disease; NAO, 10-N-nonyl acridine orange; NASH, nonalcoholic steatohepatitis; OA, oleic acid; PA, palmitic acid; PACOCF₃, palmitoyl trifluoromethyl ketone; PC, phosphatidylcholine; PI, propidium iodide; PKC, protein kinase C; PLA₂, phospholipase A₂; PTX, pertussis toxin; siRNA, small interfering RNA; TG, triglyceride; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling

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