Hepatocyte-specific deletion of group VIA calcium-independent phospholipase A2 leads to protection against MCD diet-induced NASH

Polymorphisms of phospholipase A2VIA (iPLA2β or PLA2G6) are associated with body weights and blood C-reactive protein. The role of iPLA2β/PLA2G6 in non-alcoholic steatohepatitis (NASH) is still elusive. In GASL2021 abstract, we reported that female mice with myeloid-specific PLA2G6 deletion showed exacerbated hepatic fibrosis after feeding with methionine- and choline-deficient diet (MCDD). Herein, female mice with hepatocyte- (LPla2g6−/−) specific PLA2G6 deletion were phenotyped after feeding with chow or MCDD for 3.5 weeks. LPla2g6−/−mice fed with chow displayed an attenuation of blood monocytes and elevation of anti-inflammatory/pro-resolution lipoxin A4 in plasma and liver. Compared with chow, MCDD-fed mutants showed a greater elevation of hepatic lipoxin A4. Consistently, MCDD-fed LPla2g6−/−mice showed attenuated levels of plasma alanine aminotransferase, plasma non-esterified fatty acids, blood monocytes, and hepatic triglycerides. Hepatic steatosis protection was associated with upregulation of PPARalpha and attenuated hepatic expression of PPARgamma, fatty-acid uptake, triglyceride synthesis, and de novo lipogenesis genes. LPla2g6−/−mice were also protected against MCDD-induced hepatic fibrosis associated with attenuated expression of IL-6, TNF-alpha, CD115, Collagen1alpha1, Collagen4alpha1, alpha-SMA, TIMP1, TGFbeta-1, vimentin, CHOP, p-JNK, as well as the reduction of sirus-red, alpha-SMA, and cleaved caspase 3 (+) staining. Thus, PLA2G6 inactivation specifically in myeloid cells and hepatocytes led to opposing phenotypes in female mice undergoing NASH. Mechanistically, PLA2G6 inactivation in hepatocytes may induce the mobilization of arachidonate which becomes the substrate of 12/15-lipoxygenases activated by MCDD, thus resulting in the elevation of protective lipoxin A4. Hepatocyte-specific PLA2G6 inhibitors may be further developed for treatment of this disease.