Inadequate flip-flop of phosphatidylcholine is responsible for PFIC (progressive familial intrahepatic cholestasis).

• Project/Area Number: 25670165
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: TAKATSU Hiroyuki 京都大学, 薬学研究科(研究院), 研究員 (70360576)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PFIC / P4-ATPase / フリッパーゼ / ATP8B1 / 胆汁うっ滞症

Outline of Final Research Achievements

In this study, we established an assay for phospholipid flippase activities of plasma membrane localized P4-ATPases using human cell lines stably expressing ATP8B1, ATP8B2, ATP11A, and ATP11C. ATP8B1 and ATP8B2 exhibited preferential flippase activities towards PC. Some ATP8B1 mutants found in patients of progressive familial intrahepatic cholestasis type 1 (PFIC1), a severe liver disease caused by impaired bile flow, failed to translocate PC in spite of their delivery to the plasma membrane. Moreover, incorporation of PC mediated by ATP8B1 can be reversed by simultaneous expression of ABCB4, a PC floppase mutated in PFIC3 patients. Our findings elucidate the flippase activities and substrate specificities of plasma membrane localized human P4-ATPases and suggest that phenotypes of some PFIC1 patients result from impairment of the PC-flippase activity of ATP8B1.

Research Products

• [Journal Article] Phospholipid Flippase Activities and Substrate Specificities of Human Type IV P-type ATPases Localized to the Plasma Membrane (2014)
  • Author(s): Takatsu, H., Tanaka, G., Segawa, K., Suzuki, J., Nagata, S., Nakayama, K. and Shin, H.W.
  • Journal Title: J. Biol. Chem Volume: 289 Issue: 48 Pages: 33543-33556
  • DOI: 10.1074/jbc.m114.593012
  • NAID: 120005690224
  • Peer Reviewed / Open Access
• [Presentation] ホスファチジルコリンのフリップ‧-フロップの相関性の破綻とPFIC（進行性家族性肝内胆汁うっ滞症） (2014)
  • Author(s): 高津宏之、田中雅久、中山和久、申 惠媛
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-18
• [Presentation] ATP8B1(FIC1, familial intrahepatic cholestasis 1)はフォスファチジルコリンのフリッパーゼである
  • Author(s): 高津宏之、中山和久、申 惠媛
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 脂質二重層の非対称性を調節するP4-ATPaseのリサイクリング経路における機能解析
  • Author(s): 小野夏生、高津宏之、中山和久、申 惠媛
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜