Zusammenfassung
PLA2G6 or GVIA calcium-independent PLA2 (iPLA2 beta) is identified as one of the NAFLD modifier genes in humans, and thought to be a target for NAFLD therapy. iPLA2 beta is known to play a house-keeping role in phospholipid metabolism and remodeling. However, its role in NAFLD pathogenesis has not been supported by results obtained from high-fat feeding of iPLA2 beta-null (PKO) mice. Unlike ...
Zusammenfassung
PLA2G6 or GVIA calcium-independent PLA2 (iPLA2 beta) is identified as one of the NAFLD modifier genes in humans, and thought to be a target for NAFLD therapy. iPLA2 beta is known to play a house-keeping role in phospholipid metabolism and remodeling. However, its role in NAFLD pathogenesis has not been supported by results obtained from high-fat feeding of iPLA2 beta-null (PKO) mice. Unlike livers of human NAFLD and genetically obese rodents, fatty liver induced by high-fat diet is not associated with depletion of hepatic phospholipids. We therefore tested whether iPLA2 beta could regulate obesity and hepatic steatosis in leptin-deficient mice by cross-breeding PKO with ob/ob mice to generate ob/ob-PKO mice. Here we observed an improvement in ob/ob-PKO mice with significant reduction in serum enzymes, lipids, glucose, insulin as well as improved glucose tolerance, and reduction in islet hyperplasia. The improvement in hepatic steatosis measured by liver triglycerides, fatty acids and cholesterol esters was associated with decreased expression of PPAR gamma and de novo lipogenesis genes, and the reversal of beta-oxidation gene expression. Notably, ob/ob livers contained depleted levels of lysophospholipids and phospholipids, and iPLA2 beta deficiency in ob/ob-PKO livers lowers the former, but replenished the latter particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC) that contained arachidonic (AA) and docosahexaenoic (DHA) acids. Compared with WT livers, PKO livers also contained increased PE and PC containing AA and DHA. Thus, iPLA2 beta deficiency protected against obesity and ob/ob fatty liver which was associated with hepatic fatty-acyl phospholipid remodeling. Our results support the deleterious role of iPLA2 beta in severe obesity associated NAFLD. (C) 2016 Elsevier B.V. All rights reserved.
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