Critical Role of Hepatic Fatty-Acyl Phospholipid Remodeling in Obese and Nonobese Fatty Liver Mouse Models

Polymorphisms of GVIA calcium-independent PLA2 (iPLA2β) implicate its role in plasma lipids, type-2 diabetes, and nonalcoholic fatty liver disease (NAFLD). iPLA2β is thought as a target for NAFLD therapy. We investigated the role of hepatic phospholipids in three NAFLD models: genetic Ob/Ob mice, long-term high-fat diet (HFD)-fed mice (representing obese NAFLD), and mice fed with methionine-choline-deficient (MCD) diet (representing nonobese NAFLD). A defect in hepatic fatty-acyl remodeling of phosphatidylcholine (PC) was observed in these three NAFLD models. By using iPLA2β-null mice, our profiling results revealed that the defect in PC remodeling was rescued in obese NAFLD associated with fatty liver and obesity protection. The rescue of PC remodeling and steatosis protection was not observed in MCD-fed mice. Our results indicate a critical role of hepatic PC for protection by iPLA2β inactivation, suggesting that iPLA2β inhibitors may be used as a therapy for obese but not nonobese NAFLD.