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

2014 Fiscal Year Final Research Report

• 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
• Keywords: PFIC

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.

Free Research Field

細胞生物学