| Summary: | Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA<sub>2</sub>β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA<sub>2</sub>β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We studied the role of iPLA<sub>2</sub>β on PL metabolism in non-alcoholic fatty liver disease (NAFLD). By using global deletion iPLA<sub>2</sub>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<sub>2</sub>β deficiency rescued these decreases in obese, but not in non-obese, NAFLD models. iPLA<sub>2</sub>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<sub>2</sub>β-null mice was critical for the protection against NAFLD and obesity. However, iPLA<sub>2</sub>β deletion in specific cell types such as macrophages may render liver inflammation and fibrosis, independent of steatosis protection.
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