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Bile formation: Do not ignore the role of plasma membrane–cytoskeleton linking proteins
Author(s) -
Lazaridis Konstantinos N.,
LaRusso Nicholas F.
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510370130
Subject(s) - radixin , multidrug resistance associated protein 2 , moesin , ezrin , bone canaliculus , chemistry , membrane protein , secretion , cytoskeleton , cholestasis , microbiology and biotechnology , biochemistry , biology , endocrinology , medicine , membrane , atp binding cassette transporter , cell , transporter , gene
The ezrin‐radixin‐moesin (ERM) family of proteins crosslink ac‐tin filaments and integral membrane proteins. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCMs). Here we show that Rdx(–/–) mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbiliru‐binemia in Dubin‐Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx / mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P‐glycoproteins. In vitro binding studies show that radixin associates directly with the car‐boxy‐terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.