%0 Journal Article
%T Impact of glycosylphosphatidylinositol-specific phospholipase D on hepatic diacylglycerol accumulation, steatosis, and insulin resistance in diet-induced obesity | APSselect
%A Hirofumi Nagao
%A Hitoshi Nishizawa
%A Iichiro Shimomura
%A Norikazu Maeda
%A Shigeki Masuda
%A Shiro Fukuda
%A Shunbun Kita
%A Yoshimitsu Tanaka
%A Yoshinari Obata
%A Yuri Tsugawa-Shimizu
%A Yuto Nakamura
%A Yuya Fujishima
%A [email protected]
%J American Journal of Physiology-Renal Physiology
%D 2019
%X 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 PKC¦Å 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
%U https://journals.physiology.org/doi/full/10.1152/ajpendo.00319.2018%40apsselect.2019.6.issue-1