Significance of glycosylphosphatidylinositol-specific phospholipase D in metabolic disorders

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16229
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Osaka University
• Principal Investigator: Fujishima Yuya 大阪大学, 医学系研究科, 助教 (10779789)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: GPI-PLD / 脂肪肝 / 肥満症 / 2型糖尿病 / メタボリックシンドローム

Outline of Final Research Achievements

GPI-PLD is an enzyme which specifically cleaves GPI anchors. However, the biological roles of GPI-PLD have not been elucidated. GPI-PLD mRNA was most highly expressed in liver, and hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic conditions. Mice lacking GPI-PLD (GP-KO mice) exhibited the amelioration of glucose intolerance and hepatic steatosis in diet-induced obesity model. Furthermore, diacylglycerol (DAG) content was significantly decreased in livers of GP-KO mice. In vitro experiments 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 ALT and triglyceride (TG) levels in the male subjects with metabolic syndrome.
In conclusion, up-regulation of hepatic GPI-PLD leads to DAG accumulation in liver, which may play a causal role in impaired hepatic insulin signaling and progression of fatty liver.

Free Research Field

糖尿病・内分泌・代謝学

Academic Significance and Societal Importance of the Research Achievements

肝GPI-PLDの生理・病態的な役割はこれまで未知であったが脂肪肝や糖尿病の発症・進展に関わる可能性ならびに、その想定されるメカニズムの一端を、本研究により明らかにすることができた。
GPI-PLDは酵素であることから、その阻害薬による糖尿病や脂肪肝の治療展開も期待され、新たな治療薬の開発につながる可能性が導かれた。