Distinct Roles of Myeloid- and Hepatocyte-PLA2G6 Deletion in Mice With Metabolic Dysfunction-Associated Steatotic...

Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA2β or PLA2G6) are associated with Type-2 diabetes, blood lipids and inflammation. Global deficiency in iPLA2β-null mice elicited protection against hepatic steatosis but not hepatic inflammation after high-fat diet (HFD) feeding. We aimed to determine whether HFD-induced phenotypes could be affected by PLA2G6 deficiency specifically in myeloid cells and hepatocytes.

Male control Pla2g6^flox/flox, myeloid-(Pla2g6^M-/-) and hepatocyte-(Pla2g6^Hep-/-) specific Pla2g6-deficient mice were subjected to chow or HFD feeding for 6 months. The contents of phospholipids, white blood cell counts, plasma cytokines and metabolic parameters were quantified. Hepatic inflammation, lymphopoiesis and fibrosis were evaluated by histology, immunohistochemistry, Western blot and qRT-PCR.

Increased levels of phospholipids were observed in bone marrow-derived macrophages and livers from chow-fed Pla2g6^M-/- and Pla2g6^Hep-/- mice, respectively. After HFD feeding, Pla2g6^M-/- mice displayed a further increase in hepatic recruitment of granulocytes and lymphocytes, plasma cytokines/lipids, liver inflammation/fibrosis as well as metabolic parameters including plasma lipoproteins, plasma/liver lipopolysaccharides, liver triglycerides/non-esterified free fatty acids, plasma insulin/leptin and HOMA-IR. These metabolic parameters were further increased in HFD-fed Pla2g6^Hep-/- mice; however, they were protected from hepatic programmed cell death and inflammatory fibrosis with attenuation of plasma lipids and cytokines. Remarkably, these metabolic parameters were also increased in both mutants under chow.

Myeloid- and hepatocyte-PLA2G6 deficiency elicited aggravation and protection against HFD-induced hepatic inflammation, respectively. However, PLA2G6 deficiency in both cell types exacerbated insulin resistance. PLA2G6 inactivation specifically in hepatocytes may provide a potential therapy option to alleviate diet-induced liver inflammation.