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

Abstract

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.

OSTα-OSTβ: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia

“…Ost␣-Ost␤-ASBT-expressing MDCK cells were generated and characterized as previously described. 7 Following formation of a tight monolayer (typically between days 6 and 10), the cells were refed medium B (Dulbecco's modified Eagle medium containing 1,000 mg/L D-glucose, 10% [vol/vol] fetal calf serum, and antibiotics) containing 10 mmol/L sodium butyrate to induce expression of the transfected genes. 14 Approximately 20 hours later, the cell monolayers were washed and incubated at 37°C for 10 to 60 minutes with Hank's balanced salt solution plus 10 mol/L of various radiolabeled bile acids added to the 15 and employed previously in our laboratory.…”

“…6 In contrast to the apical uptake step, the mechanism for sterol export across the basolateral membrane of these cells is not well defined. However, a recent study demonstrated that ileal basolateral bile acid export may be mediated by the Ost␣-Ost␤ heteromeric transporter, 7 a transporter that was initially identified in the liver of the little skate (Leucoraja erinacea). 8,9 In contrast to all other organic anion transporters identified to date, transport activity requires the coexpression of two distinct gene products: a predicted 340 -amino acid, 7-transmembrane domain protein (OST␣) and a putative 128 -amino acid, single-transmembrane domain ancillary polypeptide (OST␤).…”

“…8,9 The present study demonstrates that another steroid, dehydroepiandrosterone sulfate (DHEAS), is also a substrate. The recent work of Dawson and colleagues 7 indicates that Ost␣ and Ost␤ messenger RNA (mRNA) expression along the mouse gastrointestinal tract mirrors that of Asbt, and that both Ost␣ and Ost␤ proteins are localized to the basolateral surface of ileal enterocytes.…”

Bile Acids Induce Ileal Damage During Experimental Necrotizing Enterocolitis

“…The recently described heteromeric organic solute transporter (Ostα/Ostβ) may be a mechanism by which BAs then are removed from the cell and transported into portal circulation. 13 In the intestine, ASBT, IBABP, and Ostα/Ostβ are expressed predominantly in the terminal ileum,13 -16 the site of injury in NEC. In normal rat ileum, ASBT and IBABP undergo biphasic regulation; they are expressed in the fetus, down-regulated in the neonate, then up-regulated again at weaning.…”

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

“…It has been suggested that iBABP specifically interacts with hASBT, further supporting its role in bile acid transport 22 . Regarding the transport of bile acids across the basolateral membrane of enterocytes, Dawson et al reported that the heteromeric organic solute transporter Ostα-Ostβ is an ileal basolateral bile acid transporter 23 . Based on expression and transport properties of the transporter complex in various tissues and using hASBT cotransfected cells, Ostα-Ostβ may be the major mechanism for ileal basolateral bile acid transport 23 .…”