Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition.

Ho RH, Leake BF, Roberts RL, Lee W, Kim RB
J Biol Chem. 2004 279 (8): 7213-22

PMID: 14660639 · DOI:10.1074/jbc.M305782200

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.

MeSH Terms (33)

African Continental Ancestry Group Alleles Amino Acid Sequence Asian Continental Ancestry Group Bile Acids and Salts Biological Transport Biotinylation Carrier Proteins Cell Line Cell Membrane Dose-Response Relationship, Drug Electrophoresis, Polyacrylamide Gel European Continental Ancestry Group Gene Frequency Genotype Glycosylation HeLa Cells Hepatocytes Hispanic Americans Humans Microscopy, Confocal Molecular Sequence Data Organic Anion Transporters, Sodium-Dependent Plasmids Polymorphism, Genetic Polymorphism, Single Nucleotide Protein Binding Protein Structure, Tertiary Sequence Homology, Amino Acid Substrate Specificity Symporters Taurocholic Acid Vaccinia virus

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