title: Cytosolic phospholipase A(2)α protects against Fas- but not LPS-induced liver injury.
abstract: OBJECTIVE
  Cytosolic phospholipase A(2)α (cPLA(2)α) is a rate-limiting key enzyme controlling the release of arachidonic acid (AA) substrate for the synthesis of prostaglandins and leukotrienes. This study was designed to explore the role of hepatocyte cPLA(2)α in Fas-mediated liver injury, in vivo.
  
  
  METHODS
  Transgenic mice with targeted expression of cPLA(2)α under control of the albumin-promoter enhancer and wild-type mice were injected intraperitoneally with anti-Fas antibody Jo2 or lipopolysaccharide plus d-galactosamine and monitored for liver injury and survival at various time points.
  
  
  RESULTS
  The cPLA(2)α Tg mice resist Fas-induced liver failure, as reflected by the lower serum transaminase levels, fewer apoptotic hepatocytes, reduced caspase activation, and reduced PARP cleavage when compared to the matched wild type mice. Inhibition of cPLA(2)α by its pharmacological inhibitor, pyrrolidine, enhanced Jo2-induced liver injury in both cPLA(2)α Tg and wild type mice. Hepatic overexpression of cPLA(2)α increases the expression of EGFR in the liver and the EGFR inhibitor, AG1478, exacerbated Jo2-mediated liver injury. The cPLA(2)α transgenic mice develop more prominent liver tissue damage than wild-type mice after LPS/d-galactosamine injection.
  
  
  CONCLUSIONS
  Hepatocyte cPLA(2)α protects against Fas-induced liver injury and this effect is mediated at least in part through the upregulation of EGFR.
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130021, China.
authors.forename: Guiying
authors.initials: G
authors.lastname: Li
authors.forename: Weina
authors.initials: W
authors.lastname: Chen
authors.forename: Chang
authors.initials: C
authors.lastname: Han
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D015870:Gene Expression; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011799:Quinazolines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D019014:fas Receptor / Q000633:toxicity
chemical_list: D008070:Lipopolysaccharides; D011799:Quinazolines; D011994:Recombinant Proteins; D020032:Tyrphostins; D019014:fas Receptor; C101044:RTKI cpd; D005688:Galactosamine; D066246:ErbB Receptors; D054513:Group IV Phospholipases A2; D020169:Caspases