Identification of a Mutation in the Ileal Sodium-dependent Bile Acid Transporter Gene That Abolishes Transport Activity

Wong, Melissa H.; Oelkers, Peter; Dawson, Paul A.

doi:10.1074/jbc.270.45.27228

Cited by 209 publications

(168 citation statements)

References 27 publications

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“…Cloning and Characterization of the Mouse ASBT PromoterThe murine slc10A2 gene is organized in six exons spanning ϳ24 kb of DNA sequence, and its structure is identical to the human and rat SLC10A2 genes (25,31,32). Exon/intron boundaries conform to consensus motifs; the introns all began with a GT at the 5Ј splice donor sites and ended with an AG at the 3Ј-splice acceptor sites.…”

Section: Resultsmentioning

confidence: 99%

Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

Chen

Dawson

et al. 2003

Journal of Biological Chemistry

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223

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Intestinal reclamation of bile salts is mediated in large part by the apical sodium-dependent bile acid transporter (ASBT). The bile acid responsiveness of ASBT is controversial. Bile acid feeding in mice results in decreased expression of ASBT protein and mRNA. Mouse but not rat ASBT promoter activity was repressed in Caco-2, but not IEC-6, cells by chenodeoxycholic acid. A potential liver receptor homologue-1 (LRH-1) cis-acting element was identified in the bile acid-responsive region of the mouse but not rat promoter. The mouse, but not rat, promoter was activated by LRH-1, and this correlated with nuclear protein binding to the mouse but not rat LRH-1 element. The short heterodimer partner diminished the activity of the mouse promoter and could partially offset its activation by LRH-1. Interconversion of the potential LRH-1 cis-elements between the mouse and rat ASBT promoters was associated with an interconversion of LRH-1 and bile acid responsiveness. LRH-1 protein was found in Caco-2 cells and mouse ileum, but not IEC-6 cells or rat ileum. Bile acid response was mediated by the farnesoid X receptor, as shown by the fact that overexpression of a dominant-negative farnesoid X-receptor eliminated the bile acid mediated down-regulation of ASBT. In addition, ASBT expression in farnesoid X receptor null mice was unresponsive to bile acid feeding. In summary cell line-and speciesspecific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner-dependent repression of LRH-1 activation of the ASBT promoter.Reclamation of bile salts by the intestine is primarily mediated by the apical sodium-dependent bile acid transporter (ASBT) 1 located in the terminal ileum (1, 2). The bile acid responsiveness of ASBT expression, which is of fundamental importance to both cholesterol metabolism and cholestatic liver disease, is a matter of on-going controversy (3). Conflicting results have been observed in a number of laboratories, where experimental methodologies and animal species have been variable (4 -15). Positive (5, 7, 9, 11, 13-15), negative (4,6,8,12,15), and no (10) feedback regulation have been observed. Bile acid homeostasis has been perturbed by bile acid (4, 6, 8 -10, 12), sequestrant (4, 6, 8, 10), or cholesterol (10, 13, 14) feeding; by common bile duct ligation (7,10,11,15) or diversion (5, 9, 11); and by genetic modification of bile acid biosynthesis (12). Investigations have been carried out in rats (4, 5, 7, 9 -11, 15), mice (8, 12), guinea pigs (4, 6), and rabbits (13,14). Bile acid transport has been measured using intact intestine (4, 6, 11) and brush border membrane vesicles (5, 7, 9, 10, 15). ASBT expression has been quantified at the level of protein (9 -15) and messenger RNA (8,9,11,15). The complexity of the current literature reflects the difficulties of in vivo assessment of a transport system that is part of a highly integrated and tightly regulated metabolic pathway. The molecular mechanisms of bile acid responsiveness have been eluci...

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Section: Resultsmentioning

confidence: 99%

Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

Chen

Dawson

et al. 2003

Journal of Biological Chemistry

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223

183

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“…On day 1, the cells were transfected with Ost␣, Ost␤, or Ost␣-Ost␤. On day 2, the cells were lysed, and 100 g of cell protein was incubated in the absence (lanes 1, 2, 7, 8) or presence of Endo H (lanes 3, 4, 9, 10), or PNGase F (lanes 5,6,11,12). Samples were then subjected to immunoblotting analysis for Ost␣ (lanes 1-6) and Ost␤ (lanes 7-12).…”

Section: Expression and Localization Of Mouse Ost␣ And Ost␤ Inmentioning

confidence: 99%

“…The polyclonal rabbit anti-mouse Asbt antibody was raised against a synthetic peptide corresponding to amino acids 335-348 of the mouse Asbt and has been described previously (12). The polyclonal rabbit anti-human ASBT antibody was raised against the carboxyl-terminal 39 amino acids of human ASBT that was expressed as a glutathione S-transferase-ASBT fusion protein.…”

Section: Materials-[mentioning

confidence: 99%

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

Dawson

Hubbert

Haywood

et al. 2005

Journal of Biological Chemistry

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349

364

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Bile acids are transported across the ileal enterocyte brush border membrane by the well characterized apical sodium-dependent bile acid transporter (Asbt) Slc10a2; however, the carrier(s) responsible for transporting bile acids across the ileocyte basolateral membrane into the portal circulation have not been fully identified. Transcriptional profiling of wild type and Slc10a2 null mice was employed to identify a new candidate basolateral bile acid carrier, the heteromeric organic solute transporter (Ost)␣-Ost␤. By Northern blot analysis, Ost␣ and Ost␤ mRNA was detected only in mouse kidney and intestine, mirroring the horizontal gradient of expression of Asbt in the gastrointestinal tract. Analysis of Ost␣ and Ost␤ protein expression by immunohistochemistry localized both subunits to the basolateral surface of the mouse ileal enterocyte. The transport properties of Ost␣-Ost␤ were analyzed in stably transfected Madin-Darby canine kidney cells. Coexpression of mouse Ost␣-Ost␤, but not the individual subunits, stimulated Na ؉ -independent bile acid uptake and the apical-to-basolateral transport of taurocholate. In contrast, basolateral-to-apical transport was not affected by Ost␣-Ost␤ expression. Co-expression of Ost␣ and Ost␤ was required to convert the Ost␣ subunit to a mature glycosylated endoglycosidase H-resistant form, suggesting that co-expression facilitates the trafficking of Ost␣ through the Golgi apparatus. Immunolocalization studies showed that co-expression was necessary for plasma membrane expression of both Ost␣ and Ost␤. These results demonstrate that the mouse Ost␣-Ost␤ heteromeric transporter is a basolateral bile acid carrier and may be responsible for bile acid efflux in ileum and other ASBT-expressing tissues.

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“…ASBT consists of 348 amino acids (347 in rabbits) with an observed molecular weight of 43 kDa which differs from a predicted molecular weight of 38 kDa due to glycosylation 28 . The ASBT gene is localized on chromosome 13q33.…”

Section: Biology Of Asbtmentioning

confidence: 97%

Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2): A Potential Prodrug Target

2006

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A major hurdle impeding the successful clinical development of drug candidates can be poor intestinal permeability. Low intestinal permeability may be enhanced by a prodrug approach targeting membrane transporters in the small intestine. Transporter specificity, affinity, and capacity are three factors in targeted prodrug design. The human apical sodium dependent bile acid transporter (SLC10A2) belongs to the solute carrier family (SLC) of transporters and is an important carrier protein expressed in the small intestine. In spite of appearing to be an excellent target for prodrug design, few studies have targeted human apical sodium dependent bile acid transporter (hASBT) to improve oral bioavailability. The review discusses bile acids including their chemistry and their absorptive disposition. Additionally, hASBT-mediated prodrug targeting is discussed, including QSAR, in-vitro models for hASBT assay, and the current progress in utilizing hASBT as a drug delivery target.

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Identification of a Mutation in the Ileal Sodium-dependent Bile Acid Transporter Gene That Abolishes Transport Activity

Cited by 209 publications

References 27 publications

Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2): A Potential Prodrug Target

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