Rescue of Hepatic Phospholipid Remodeling Defect in iPLA(2)β-Null Mice Attenuates Obese but Not Non-Obese Fatty Liver

Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA(2)β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA(2)β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We studied the role of iPLA(2)β on PL metabolism in non-alcoholic fatty liver disease (NAFLD). By using global deletion iPLA(2)β-null mice, we investigated three NAFLD mouse models; genetic Ob/Ob and long-term high-fat-diet (HFD) feeding (representing obese NAFLD) as well as feeding with methionine- and choline-deficient (MCD) diet (representing non-obese NAFLD). A decrease of hepatic PLs containing monounsaturated- and polyunsaturated fatty acids and a decrease of the ratio between PLs and cholesterol esters were observed in all three NAFLD models. iPLA(2)β deficiency rescued these decreases in obese, but not in non-obese, NAFLD models. iPLA(2)β deficiency elicited protection against fatty liver and obesity in the order of Ob/Ob › HFD » MCD. Liver inflammation was not protected in HFD NAFLD, and that liver fibrosis was even exaggerated in non-obese MCD model. Thus, the rescue of hepatic PL remodeling defect observed in iPLA(2)β-null mice was critical for the protection against NAFLD and obesity. However, iPLA(2)β deletion in specific cell types such as macrophages may render liver inflammation and fibrosis, independent of steatosis protection.