Myeloid- and hepatocyte-specific deletion of group VIA calcium-independent phospholipase A2 leads to opposing phenotypes during HFD-induced NASH

Background:Global deletion of PLA2G6 led to attenuation of hepatic steatosis but not inflammation after high-fat diet (HFD) feeding (BBA2019). We generated myeloid- (Pla2g6M-/-) and hepatocyte-specific (Pla2g6Hep-/-) KO mice, and they showed opposing phenotypes in non-obese NASH (BBA2023). Herein, we aimed to phenotype these KO in HFD-induced NASH.

Methods:Male Pla2g6flox (controls) and KO mice at 6 months old were fed with chow or HFD for 6 months. Livers were harvested for IHC and WB analyses. White-blood-cell counts, plasma lipids and cytokines were analyzed.

Results:Despite of reduction of body weights, HFD-fed Pla2g6M-/- and Pla2g6Hep-/- respectively exhibited worsen and improved levels of plasma lipids and NAFLD activity scores. Under chow or HFD, Pla2g6M-/- mice exhibited a significant increase in granulocyte and eosinophil populations associated with increased neutrophils-to-lymphocytes ratio, while lymphocytes, red blood cells, and hematocrits were decreased. Under HFD, Pla2g6M-/- showed a further increase in plasma IL-6 and IL-4, while Pla2g6Hep-/- showed attenuation of TNF-α, MCP-1, IL-13, and KC/CXCL1 as well as IHC positivity of liver F4/80 and eosinophil-cationic-protein. The latter was already observed in chow-fed Pla2g6M-/- mice. While Pla2g6M-/- mice under chow or HFD showed significant up-regulation of hepatic α-SMA, Pla2g6Hep-/- mice under HFD showed down-regulation of hepatic collagen IV.

Conclusions:Myeloid-Pla2g6 deficiency led to systemic and hepatic inflammation, anemia, and liver fibrosis, which was exacerbated by HFD. On the other hand, hepatocyte-Pla2g6 deficiency conferred NAFLD protection. Our study illustrates distinct contributions of cell-specific PLA2G6 inactivation to NAFLD/NASH, and provides therapeutic strategies for treatment of this disease.

Publication History

Article published online:
20 January 2025