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Familial intrahepatic cholestasis 1: Studies of localization and function
Author(s) -
Ujhazy Peter,
Ortiz Daniel,
Misra Suniti,
Li Shohua,
Moseley James,
Jones Hugh,
Arias Irwin M.
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.27663
Subject(s) - cholestasis , apical membrane , translocase , biology , biochemistry , microbiology and biotechnology , chemistry , endocrinology , membrane , chromosomal translocation , gene
Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy‐dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain. In the small intestine, Fic1 was localized to the apical membrane of epithelial cells. The distribution of Fic1 in liver plasma membrane fractions from control and taurocholate‐treated rats correlated positively with adenosine triphosphate (ATP)‐dependent aminophospholipid (phosphatidyl‐serine) translocase activity. In canalicular membrane vesicles, translocase activity had an initial velocity of 3.3 nmol phosphatidylserine (PS) translocated per milligram of protein per minute and a K m (ATP) = 1.2 mmol/L; was inhibited by vanadate, N ‐ethylmaleimide, sodium azide, and calcium; and was unidirectional ( i.e., from the outer to the inner canalicular plasma membrane leaflet). Transient transfection of CHOK1 cells with FIC1 cDNA resulted in appearance of FIC1 in membrane preparations and energy‐dependent PS translocation in cells. These studies indicate that FIC1 is a canalicular P‐type ATPase that participates in maintaining the distribution of aminophospholipids between the inner and outer leaflets of the plasma membrane. How this process produces cholestasis is under study.