Deficiency of Group IVA Phospholipase A₂ in Collagen-Producing Cells Alleviates the Aggravated Hepatic Fibrosis in High-Fat Diet-Fed Mice after Returning to a Normal Diet

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Hepatic fibrosis, a primary feature of non-alcoholic steatohepatitis (NASH), develops with inflammation and subsequent activation of hepatic stellate cells (HSCs), the main extracellular matrix-producing cells. Currently, no approved pharmacotherapy is available to treat hepatic fibrosis, even under dietary intervention. The activation of cultured HSCs has been shown to be attenuated by pharmacological inhibition of group IVA phospholipase A₂ (IVA-PLA₂), an enzyme initiating the generation of lipid proinflammatory mediators. We examined the potential utility of IVA-PLA₂ of HSCs as a therapeutic target for hepatic fibrosis in NASH under dietary modification using collagen-producing cell-specific IVA-PLA₂-conditional knockout mice fed a high-fat diet and then returned to a normal one. Apparent hepatic fibrosis and the accumulation of hepatic lipid droplets developed in the IVA-PLA₂-conditional knockout mice on a high-fat diet for nine weeks to a similar degree as in control mice. Most of the lipid droplets disappeared five weeks after switching the diet back to a normal one in both genetic mice. In contrast, the hepatic fibrosis in control mice still progressed even after changing back to a normal diet. However, deficiency of IVA-PLA₂ in collagen-producing cells alleviated the aggravated hepatic fibrosis under dietary modification. Our results revealed that the protective effects of an HSC-specific IVA-PLA₂ deficiency on fibrogenesis appear after switching the diet from a high-fat one back to a normal one, supporting the promising beneficial effects of the inhibition of IVA-PLA₂ on progressive hepatic fibrosis under dietary intervention in NASH treatment.