| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Outline of Final Research Achievements |
Progressive familial intrahepatic cholestasis (PFIC) is a severe liver disease caused by impaired bile flow. PFIC type 1 (PFIC1) results from mutations in the ATP8B1 (flippase) protein. Although ATP8B1 has been hypothesized to mediate translocation of phosphatidylserine (PS) at the plasma membrane, it is unclear whether a defect in the phospholipid flippase activity of ATP8B1 is related to cholestasis. In this study, we found that ATP8B1 mediates the translocation of phosphatidylcholine (PC), but not PS, at the plasma membrane. The majority of missense mutations found in progressive familial intrahepatic cholestasis1 (PFIC1) patients reduced expression of ATP8B1 at the plasma membrane. Importantly, however, some missense mutants failed to translocate PC, although they were expressed normally at the plasma membrane. These findings implicate defects in the PC flippase activity of ATP8B1 in cholestasis and provide important insights into the pathophysiological mechanisms of PFIC1.
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