Exploration of enhancer of ABCB4 to enable treatment of liver injury in cholestasis and arteriosclerosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K14918
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kobe Pharmaceutical University (2019-2020); Shiga University of Medical Science (2018)
• Principal Investigator: IKEDA Yoshito 神戸薬科大学, 薬学部, 助教 (40736980)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: リン脂質 / 胆汁酸 / ABCトランスポーター

Outline of Final Research Achievements

Bile salts are associated with phospholipid, the main constituents of bile, in mixed micells. The association of bile salts and phospholipid protects hepatocytes from the cytotoxicity of bile salts. ABCB4, a member of the ATP binding cassette transporter family, is present in the canalicular membrane of hepatocytes, and plays an essential role in the secretion of phospholipids into bile. In this study, we searched enhancer of ABCB4-mediated phospholipid efflux, and tried elucidation of its mechanism. We showed that ABCB4-mediated phospholipid efflux was significantly stimulated by taurine-conjugated hyodeoxycholate using cultured cells and experimental animals. In addition, it is conceivable that the enhancing effect of taurine-conjugated hyodeoxycholate on the ABCB4-mediated phospholipid efflux may be due to the strong mixed micelle formation ability.

Free Research Field

脂質生化学

Academic Significance and Societal Importance of the Research Achievements

ABCB4が疎水性の高いリン脂質を親水的環境である胆汁中へと排出する分子機序の詳細については不明であった。これはHDLの形成に関与するABCA1など、他の脂質トランスポーターにおいても共通の問題点である。本研究によって、リン脂質との混合ミセル形成能が高いタウリン抱合型ヒオデオキシコール酸が、リン脂質の優れたアクセプター分子として作用することが示唆された。これらの知見が、ABCB4だけでなく、他の脂質トランスポーターの輸送機序解明にも役立ち、関連する疾患の治療薬開発につながることが期待される。