Article

Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis

Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, E RAE 09, 8091 Zürich, Switzerland.
Journal of Hepatology (Impact Factor: 10.4). 09/2005; 43(3):536-43. DOI: 10.1016/j.jhep.2005.05.020
Source: PubMed

ABSTRACT Inherited dysfunction of the bile salt export pump BSEP (ABCB11) causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively. We functionally characterized novel ABCB11 mutations encountered in two patients with a PFIC2 and a BRIC2 phenotype, respectively.
BSEP expression was determined in liver biopsies by immunohistochemistry. ABCB11 mutations were functionally characterized by taurocholate transport in SF9 cells transfected with human ABCB11.
The PFIC2 patient was compound heterozygous for a splicing mutation in intron 4 ((+3)A > C) combined with an early stop codon at position 930 (R930X), while the BRIC2 patient was compound heterozygous for two nonsynonymous mutations in exon 9 (E297G) and exon 12 (R432T), respectively. Hepatic BSEP expression was absent in PFIC2 and preserved in BRIC2. In BRIC2, taurocholate transport was decreased to 13% and 20% of reference levels for R432T and E297G, respectively.
The intron 4 (+3)A > C, R930X and R432T represent previously undescribed mutations of the ABCB11 gene that confer a PFIC2 and a BRIC2 phenotype, respectively. By combining functional in-vitro characterization with immunohistochemical detection of variant BSEP we provide direct evidence for the role of ABCB11 mutations in the pathogenesis of different forms of intrahepatic cholestasis.

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    ABSTRACT: In recent years the discovery of a number of major transporter proteins expressed in the liver and intestine specifically involved in bile acid transport has led to improved understanding of bile acid homeostasis and the enterohepatic circulation. Sodium (Na(+))-dependent bile acid uptake from portal blood into the liver is mediated primarily by the Na(+) taurocholate co-transporting polypeptide (NTCP), while secretion across the canalicular membrane into the bile is carried out by the bile salt export pump (BSEP). In the ileum, absorption of bile acids from the lumen into epithelial cells is mediated by the apical Na(+) bile salt transporter (ASBT), whereas exit into portal blood across the basolateral membrane is mediated by the organic solute transporter alpha/beta (OSTalpha/beta) heterodimer. Regulation of transporter gene expression and function occurs at several different levels: in the nucleus, members of the nuclear receptor superfamily, regulated by bile acids and other ligands are primarily involved in controlling gene expression, while cell signalling events directly affect transporter function, and subcellular localization. Polymorphisms, dysfunction, and impaired adaptive responses of several of the bile acid transporters, e.g. BSEP and ASBT, results in liver and intestinal disease. Bile acid transporters are now understood to play central roles in driving bile flow, as well as adaptation to various pathological conditions, with complex regulation of activity and function in the nucleus, cytoplasm, and membrane.
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    • "The bile salt export pump mediates uphill canalicular bile acid secretion [2]. Inherited dysfunction of the bile salt export pump causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively [3]. Inborn defects in its function cause intrahepatic cholestasis in infants; inhibition of its function by drugs causes hepatotoxicity [2]. "
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