Impact of glycosylphosphatidylinositol-specific phospholipase D on hepatic diacylglycerol accumulation,steatosis,and insulin resistance in diet-induced obesity.

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme which specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, Type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI-PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in liver. GPI-PLD mRNA was most highly expressed in liver, and hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose (HF/HS) diet. Furthermore, diacylglycerol (DAG) content was significantly decreased and PKCε activity was suppressed in livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI-PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (ALT) (R = 0.37, P = 0.0006) and triglyceride (TG) (R = 0.34, P = 0.001) levels in the male subjects with metabolic syndrome. In conclusion, up-regulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and progression of NAFLD.