Cytosolic phospholipase A(2)α protects against Fas- but not LPS-induced liver injury.

BACKGROUND & AIMS: 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.