Ethnicity-dependent Polymorphism in Na+-taurocholate Cotransporting Polypeptide (SLC10A1) Reveals a Domain Critical for Bile Acid Substrate Recognition
Year: 2004
Type: article
Abstract: The key transporter responsible for hepatic uptake of bile acids from portal circulation is Na+-taurocholate cotransporting polypeptide (NTCP, SLC10A1). This transporter is thought to be critical for the maintenance of enterohepatic recirculation of bile acids and hepatocyte function. Therefore, functionally relevant polymorphisms in this transporter would be predicted to have an important impact on bile acid homeostasis/liver function. However, little is known regarding genetic heterogeneity in NTCP. In this study, we demonstrate the presence of multiple single nucleotide polymorphisms in NTCP in populations of European, African, Chinese, and Hispanic Americans. Specifically four nonsynonymous single nucleotide polymorphisms associated with a significant loss of transport function were identified. Cell surface biotinylation experiments indicated that the altered transport activity of T668C (Ile223-->Thr), a variant seen only in African Americans, was due at least in part to decreased plasma membrane expression. Similar expression patterns were observed when the variant alleles were expressed in HepG2 cells, and plasma membrane expression was assessed using immunofluorescence confocal microscopy. Interestingly the C800T (Ser267-->Phe) variant, seen only in Chinese Americans, exhibited a near complete loss of function for bile acid uptake yet fully normal transport function for the non-bile acid substrate estrone sulfate, suggesting this position may be part of a region in the transporter critical and specific for bile acid substrate recognition. Accordingly, our study indicates functionally important polymorphisms in NTCP exist and that the likelihood of being carriers of such polymorphisms is dependent on ethnicity.
Source: Journal of Biological Chemistry
Authors: Richard H. Ho, Brenda F. Leake, Richard L. Roberts, Wooin Lee, Richard B. Kim
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G120018185, G2007841888, The PharmGKB: Catalyzing Research in Pharmacogenetics, G3722609264, G3989539122, G4513176822, G46180382, G5006813979, G599787681, Pharmacogenomics of Arrhythmia Therapy, DETERMINANTS OF INDIVIDUAL RESPONSIVENESS TO DRUGS, Vanderbilt Clinical Oncology Research Career Development Award, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant
OpenAlex ID: W2046507147