The role of ILDR2 in biomembrane phospholipids and hepatic steatosis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08914
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Watanabe Kazuhisa 自治医科大学, 医学部, 講師 (60724416)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ILDR2 / 脂肪肝 / リン脂質

Outline of Final Research Achievements

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and increases the risk for liver cirrhosis and cancer. A diabetes susceptibility gene, Ildr2, encodes a transmembrane protein localized to the ER membrane whose physiological functions are unknown. We previously identified ILDR2 interaction protein, MBOAT7, which mediates acyl-chain remodeling of phosphatidylinositols (PIs). We hypothesized that ILDR2 may influence hepatic Pl composition in NAFLD. In LKO-ILDR2 mice fed on the choline-deficient amino acid-defined high fat diet (CDAHFD) compared to AAV-GFP injected Ildr2 floxed (GFP-flox) mice fed on the CDAHFD, liver triglyceride content was significantly increased by LKO-ILDR2 mice compared to GFP-flox mice, hepatic PI was significantly increased. Hepatic PI was significantly decreased in OX-ILDR2 mice. Manipulation of hepatic ILDR2 expression is associated with changes in PI molecular species in the liver.

Free Research Field

代謝学

Academic Significance and Societal Importance of the Research Achievements

脂肪肝は２型糖尿病の重要なリスク因子に留まらず、メタボリックシンドロームと相まった脂肪肝炎からの肝線維化は動脈硬化疾患を増悪させるため、有効な治療法の開発が強く求められている。我々はILDR2の局在や結合タンパク質の同定、さらにノックアウトマウスを解析することにより個体レベルでのILDR2の意義と脂肪肝における影響を明らかにした。この研究過程で、ILDR2が肝臓中リン脂質の質的変化に関与し、脂肪肝発症や肝線維化の進展に関与することを示した。脂肪肝の有効な治療法はないため、ILDR2の機能解明は脂肪肝の治療法開発の分子基盤になると期待される。