J. Lipid Res.
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A more recent version of this article appeared on January 1, 2008

Papers In Press, published online ahead of print October 18, 2007
J. Lipid Res., doi:10.1194/jlr.M700184-JLR200
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Submitted on April 16, 2007
Revised on October 17, 2007
Accepted on October 18, 2007

Lysophosphatidylcholine as a death effector in lipoapoptosis of hepatocytes

Myoung Sook Han, Sun Young Park, 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

Dept. of Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710

Corresponding Author: mslee{at}smc.samsung.co.kr

Pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH employing 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 conversion product(s) 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 (siRNA) for Ca2+-independent PLA2(iPLA2) inhibited lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA2 inhibitors. Pertussis toxin (PTX) 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 (OA) inhibited PA-induced hepatocyte death by diverting PA to triglyceride (TG) and decreasing LPC content, suggesting 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 an important death effector in lipoapoptosis of hepatocytes and suggest potential therapeutic values of PLA2 inhibitors or GPCR/Galpha i inhibitors in NASH.


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