Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

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 (PLA ₂) 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 Gα_i mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/Gα_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/ Gα_i inhibitors in NASH.