The heteromeric organic solute transporter, OSTα–OSTβ/SLC51: A transporter for steroid-derived molecules

Abstract

The organic solute transporter alpha-beta (OSTα-OSTβ) is one of the newest members of the solute carrier family, designated as SLC51, and arguably one of the most unique. The transporter is composed of two gene products encoded by SLC51A and SLC51B that heterodimerize to form the functional transporter complex. SLC51A encodes OSTα, a predicted 340-amino acid, 7-transmembrane (TM) domain protein, whereas SLC51B encodes OSTβ, a putative 128-amino acid, single-TM domain polypeptide. Heterodimerization of the two subunits increases the stability of the individual proteins, facilitates their post-translational modification, and is required for delivery of the functional transporter complex to the plasma membrane. There are no paralogues for SLC51A or SLC51B in any genome that has been examined. The transporter functions via a facilitated diffusion mechanism, and can mediate either efflux or uptake depending on the electrochemical gradient of its substrates. Overall, characterization of the transporter's substrate specificity, transport mechanism, tissue distribution, subcellular localization, and transcriptional regulation as well as the phenotype of the recently generated Slc51a-deficient mice have revealed that OSTα-OSTβ plays a central role in the transport of bile acids, conjugated steroids, and structurally-related molecules across the basolateral membrane of many epithelial cells. In particular, OSTα-OSTβ appears to be essential for intestinal bile acid absorption, and thus for dietary lipid absorption.

Intestinal transport and metabolism of bile acids

“…Whereas several candidate intestinal basolateral membrane transporters were identifi ed over the years ( 10 ), the preponderance of evidence indicates that the heteromeric transporter OST ␣ -OST ␤ is responsible for the majority of intestinal basolateral membrane bile acid export ( 87,88 ). Support for this role of OST ␣ -OST ␤ , a heterodimer consisting of a 352-amino acid polytopic membrane protein (OST ␣ ) and a 182-amino acid predicted type I membrane protein (OST ␤ ), includes: 1 ) intestinal expression that overlaps the ASBT, 2 ) plasma membrane localization restricted to the basolateral aspect of the enterocyte, 3 ) transport specifi city that includes the major bile acid species, 4 ) expression that is strongly induced by bile acids acting through FXR, and 5 ) impaired intestinal bile acid absorption and altered bile acid metabolism in OST ␣ -null mice ( 18,19 ).…”

“…In that study, mucosal-to-serosal transport of taurocholate was signifi cantly reduced in ileal gut sacs prepared from male and female IBABP-null mice. But the in vivo phenotype was complex, where loss of IBABP was associated with reduced hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) expression and increased fecal bile acid excretion widely expressed and is abundant in tissues important for steroid homeostasis ( 88 ). Because OST ␣ -OST ␤ also transports endogenous small molecules such as prostaglandins, neurosteroids, and steroid sulfates ( 109,110 ), it is possible that the intestinal adaptation is a response to alterations in transport of a non-bile acid substrate.…”

“…Alternatively, it is possible that OST ␣ -OST ␤ has other cellular functions besides solute transport. Although no evidence for such a role has been found in mammalian systems ( 87,88 ), a primitive OST ␣ -like protein identifi ed in C. elegans was shown to regulate intracellular membrane traffi cking and the morphology and protein composition of sensory cilia ( 113 ). Finally, no inherited phenotypic defects in the human OST ␣ or OST ␤ genes have been identifi ed, and an OST ␤ -null mouse has not yet been reported.…”

Progress in the Molecular Characterization of Hepatobiliary Transporters

“…Basolateral ATP-dependent efflux pumps (shown in green) include MRP3 (ABCC3), MRP4 (ABCC4), and MRP6 (ABCC6). OSTα/β is a heterodimeric protein mediating the facilitated diffusion of the efflux or uptake of bile acids, conjugated steroids, and structurally related molecules [67] . Only some of the substrates accepted by the transporter proteins are indicated in this scheme.…”

Identification of novel inhibitors of the amino acid transporter B0AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes

“…CHO cells do not express detectable amounts of ACE2 (Iwata et al, 2009) to replace collectrin. Heteromeric design of transporters is a common occurrence (Ballatori et al, 2013;Fotiadis et al, 2013;Halestrap, 2013), which needs to be taken into consideration when designing cell lines for HTS. Incidentally, the substrate specificity of B 0 AT1 is very similar to that of the endogenous transporter, which is most likely the hamster isoform of LAT2.…”