Xu_2026_Front.Immunol_17_1839554

Group VIA calcium-independent phospholipaseA2 (iPLA2beta or PLA2G6) is a homeostatic enzyme involved in basal glycerophospholipid metabolism. The mutations in the PLA2G6 gene lead to heterogenous neurodegenerative disorders. Global PLA2G6 inactivation in iPLA2beta-null mice exhibited liver fibrosis and intestinal atrophy when they reached an advanced age at 20-22 months old. Here, we analyzed the phenotypes of iPLA2beta-null mice which happened to be exposed to natural pathogens in our animal facility. Compared with wild-type, male iPLA2beta-null mice at 9-14 months of age exhibited reduced body, liver, and subcutaneous fat weights concomitant with decreased hepatic triacylglycerol and decreased expression of de novo lipogenesis genes. Hepatocytes from male mutants were sensitive to apoptosis induced by palmitic acid. Male but not female mutants displayed attenuation of hepatic lipid synthesis; however hepatic fibrosis was increased in mutants of both sexes. Hepatic apoptosis was also increased in mutants of both sexes, and they were susceptible to endotoxin-induced liver injury. Hence, global PLA2G6 inactivation combined with natural infection accelerates progression of chronic liver disease in both male and female mice with male-biased alteration of hepatocellular glycerolipid metabolism.