| Project/Area Number |
18K16229
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| 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 / XOR / 動脈硬化症 / 糖尿病 / 肥満 / ２型糖尿病 / インスリン抵抗性 / ジアシルグリセロール |
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| 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.
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| 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。
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