[Inhibition of Group IVA Phospholipase A₂ as a Novel Therapeutic Strategy for Nonalcoholic Steatohepatitis].

Nonalcoholic steatohepatitis (NASH) is a lifestyle-related disease characterized by hepatic fibrosis with the accumulation of fat and inflammation and can progress to cirrhosis or hepatocellular carcinoma. However, effective pharmacotherapeutic strategies for hepatic fibrosis in NASH remain to be established. Among the initiators of inflammation, we have been investigating the possible involvement of group IVA phospholipase A₂ (IVA-PLA₂), which catalyzes the initial step in the generation of lipid mediators, including eicosanoids and lysophospholipids, in the progression of hepatic fibrosis. We have recently demonstrated that a lack of IVA-PLA₂ alleviates hepatic fibrosis in NASH model mice fed a high-fat and high-cholesterol diet and in CCl₄-treated mice. CCl₄-induced hepatic fibrosis was also prevented by the administration of an orally active, specific IVA-PLA₂ inhibitor even after hepatic fibrosis had developed. Based on these findings suggesting that IVA-PLA₂ mediates the cellular responses contributing to the progression of hepatic fibrosis, we have been exploring which types of cells in the liver are involved in IVA-PLA₂-mediated hepatic fibrosis using cell-specific IVA-PLA₂ knockout mice. The preliminary experimental results suggest that IVA-PLA₂ in endothelial cells, but not monocyte-derived cells, plays a role, in part, in the hepatic stellate cell-mediated progression of hepatic fibrosis. In this paper, we discuss the possibility that IVA-PLA₂ and/or its related molecules are candidate pharmacotherapeutic targets for NASH treatment.

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