title: Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes.
abstract: 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 A(2) (PLA(2)) inhibitors blocked PA-induced hepatocyte death, suggesting an important role for PLA(2) and its product lysophosphatidylcholine (LPC). Small interfering RNA for Ca(2+)-independent phospholipase A(2) (iPLA(2)) inhibited the lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA(2) inhibitors. Pertussis toxin or dominant-negative Galpha(i) mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/Galpha(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 PLA(2) inhibitors or GPCR/Galpha(i) inhibitors in NASH.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Myoung Sook
authors.initials: MS
authors.lastname: Han
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.forename: Koei
authors.initials: K
authors.lastname: Shinzawa
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.forename: Kun Wook
authors.initials: KW
authors.lastname: Chung
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Choon Hyuck
authors.initials: CH
authors.lastname: Kwon
authors.forename: Kwang-Woong
authors.initials: KW
authors.lastname: Lee
authors.forename: Joon-Hyoek
authors.initials: JH
authors.lastname: Lee
authors.forename: Cheol Keun
authors.initials: CK
authors.lastname: Park
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Chung
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Ji-Jing
authors.initials: JJ
authors.lastname: Yan
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Song
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019301:Oleic Acid; D019308:Palmitic Acid; D045304:Cytochromes c; D054467:Phospholipases A2