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Functional Characterization of Polymorphic Variants in the Human Apical Sodium‐dependent Bile Acid Transporter (ASBT; SLC10A2)
Author(s) -
Ho Richard H.,
Leake Brenda F.,
Dawson Paul A.,
Kim Richard B.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1132.7
Subject(s) - enterohepatic circulation , bile acid , fgf19 , homeostasis , biology , nonsynonymous substitution , transporter , medicine , endocrinology , biochemistry , gene , fibroblast growth factor , receptor , genome
The apical sodium‐dependent bile acid transporter (ASBT) mediates the uptake of bile acids into intestinal enterocytes, supporting a critical role in normal bile acid homeostasis and maintenance of enterohepatic recirculation. Complete loss of function mutations in ASBT are associated with primary bile acid malaborption, characterized by diarrhea, steatorrhea, interruption of bile acid enterohepatic circulation, and reduced plasma cholesterol levels. We identified 6 nonsynonymous polymorphic variants within the exonic regions of the SLC10A2 gene from DNA derived from a large number of ethnically diverse healthy subjects. In general, variants tended to be infrequent and ethnic‐dependent; only one variant, 511GT (Ala171Ser), was found with a relatively common allele frequency (6.0%), in European‐Americans. A recombinant vaccinia‐based system was utilized to heterologously express wild‐type and variant ASBT variants in HeLa cells for functional studies using radiolabeled taurocholate as a substrate. Two variants, 292GA (Val98Ile) and 431GA (Cys144Tyr), were associated with significantly impaired taurocholate transport activity in vitro compared to wild‐type ASBT. Accordingly, polymorphisms in SLC10A2 may have important functional implications to normal bile acid homeostasis and enterohepatic recirculation. This work was supported in part by NIH grants GM54724 (RBK) and GM81363 (RHH).