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

Abstract

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme that 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 the liver. GPI-PLD mRNA was most highly expressed in the liver, and the 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 diet. Furthermore, diacylglycerol (DAG) content was significantly decreased, and PKCε activity was suppressed in the 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 (R = 0.37, P = 0.0006) and triglyceride (R = 0.34, P = 0.001) levels in male subjects with metabolic syndrome. In conclusion, upregulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in the liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and the progression of NAFLD.

Structure-function relationships of HDL in diabetes and coronary heart disease

“…On the one hand, overexpression of hepatic GPLD1 was found to improve oral glucose tolerance and to reduce serum triglyceride catabolism in mice (51,52). On the other hand, the KO of Phld in mice ameliorated glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet (53). Cross-sectional studies found increased plasma levels of GPLD1 in subjects with prediabetes compared with normoglycemic subjects (54) and in patients with diabetes mellitus type 1 compared with both normoglycemic subjects and T2DM patients (55).…”

Biosynthesis and biology of mammalian GPI-anchored proteins

“…Diacylglycerol might activate PKCε, which in turn binds to the insulin receptor and inhibits its tyrosine kinase activity, leading to insulin resistance. GPI-PLD knockout ameliorated glucose intolerance and hepatic steatosis under a high-fat and high-sucrose diet through a reduction of diacylglycerol and a subsequent decrease of PKCε activity [134].…”

Interaction of Full-Length Glycosylphosphatidylinositol-Anchored Proteins with Serum Proteins and Their Translocation to Cells In Vitro Depend on the (Pre-)Diabetic State in Rats and Humans

“…Soon after identification of GPLD1 in rodent and human serum and liver, the regulation of its amount and activity by various metabolism-related factors has attracted much interest. Typically, upregulation of GPLD1 hepatic protein expression and serum level in the diabetic state was found, such as for spontaneously type I diabetic mice [75], NOD and low-dose Streptozotocin-induced diabetic CD-1 mice [54], db/db mice [76], Streptozotocininduced diabetic mice [76] and rats [77,78], and mice fed with high-fat and high-sucrose diet [76]; and for patients with non-alcoholic steatohepatitis [79], latent autoimmune diabetes in adults [80], type 1 diabetes [80], insulin-resistance [81], and type 2 diabetes [82]. Downregulation of GPLD1 hepatic expression was reported for obese nondiabetic women on a low-fat diet with re-gain in insulin sensitivity [83].…”