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1.  The heteromeric organic solute transporter, OSTα–OSTβ/SLC51: A transporter for steroid-derived molecules ☆ 
Molecular aspects of medicine  2013;34(0):10.1016/j.mam.2012.11.005.
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.
doi:10.1016/j.mam.2012.11.005
PMCID: PMC3827772  PMID: 23506901
OSTα–OSTβ; Bile acids; FGF15; FXR; Slc51a−/− mice; Steroids
2.  Neurosteroid transport by the organic solute transporter OSTα-OSTβ 
Journal of neurochemistry  2010;115(1):220-233.
A variety of steroids, including pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS) are synthesized by specific brain cells, and are then delivered to their target sites, where they exert potent effects on neuronal excitability. The present results demonstrate that [3H]DHEAS and [3H]PREGS are relatively high affinity substrates for the organic solute transporter, OSTα–OSTβ, and that the two proteins that constitute this transporter are selectively localized to steroidogenic cells in the cerebellum and hippocampus, namely the Purkinje cells and cells in the CA region in both mouse and human brain. Analysis of Ostα and Ostβ mRNA levels in mouse Purkinje and hippocampal cells isolated via laser capture microdissection supported these findings. In addition, Ostα-deficient mice exhibited changes in serum dehydroepiandrosterone (DHEA) and DHEAS levels, and in tissue distribution of administered [3H]DHEAS. OSTα and OSTβ proteins were also localized to the zona reticularis of human adrenal gland, the major region for DHEAS production in the periphery. These results demonstrate that OSTα-OSTβ is localized to steroidogenic cells of the brain and adrenal gland, and that it modulates DHEA/DHEAS homeostasis, suggesting that it may contribute to neurosteroid action.
doi:10.1111/j.1471-4159.2010.06920.x
PMCID: PMC2939961  PMID: 20649839
Organic solute transporter; neurosteroid transport; pregnenolone sulfate; dehydroepiandrosterone sulfate; Purkinje cells; CA region of the hippocampus
3.  Ost alpha-Ost beta: A key membrane transporter of bile acids and conjugated steroids 
The organic solute and steroid transporter, Ost alpha-Ost beta, is an unusual heteromeric carrier that appears to play a central role in the transport of bile acids, conjugated steroids, and structurally-related molecules across the basolateral membrane of many epithelial cells. The transporter’s substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of the recently characterized Ost alpha-deficient mice all strongly support this model. Ost alpha-Ost beta is composed of a predicted 340-amino acid, 7-transmembrane (TM) domain protein (Ost alpha) and a putative 128-amino acid, single-TM domain polypeptide (Ost beta). Heterodimerization of the two subunits increases the stability of the individual proteins, facilitates their post-translational modifications, and is required for delivery of the functional transport complex to the plasma membrane. Ost alpha and Ost beta are expressed in nearly all human tissues that have been examined, but are most abundant in the small intestine, kidney, liver, testis, adrenal gland and other steroidogenic tissues. Ost alpha-Ost beta substrates include bile acids, steroids (estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, and digoxin), and prostaglandin E2, indicating a role of Ost alpha-Ost beta in the disposition of key cellular metabolites and signaling molecules. Transport occurs by a facilitated diffusion mechanism, and thus Ost alpha-Ost beta can mediate cellular efflux or uptake depending on that substrate’s electrochemical gradient. Additional strong evidence for a role of Ost alpha-Ost beta in sterol homeostasis was provided by recent studies in Ost alpha-deficient mice. These mice display a marked defect in intestinal bile acid and conjugated steroid absorption; a decrease in bile acid pool size and serum bile acid levels; altered intestinal, hepatic and renal disposition of known substrates of the transporter; and altered serum triglyceride, cholesterol, and glucose levels. Taken together, these observations indicate that Ost alpha-Ost beta is essential for bile acid and sterol disposition, and suggest that the carrier may be involved in human conditions related to imbalances in bile acid or lipid homeostasis.
PMCID: PMC2694352  PMID: 19273238
Conjugated steroids; bile acid transport; FXR; Ost alpha-Ost beta; Ost alpha−/− mice
4.  The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter*† 
The Journal of biological chemistry  2004;280(8):6960-6968.
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)α-Ostβ. By Northern blot analysis, Ostα and Ostβ mRNA was detected only in mouse kidney and intestine, mirroring the horizontal gradient of expression of Asbt in the gastrointestinal tract. Analysis of Ostα and Ostβ protein expression by immunohistochemistry localized both subunits to the basolateral surface of the mouse ileal enterocyte. The transport properties of Ostα-Ostβ were analyzed in stably transfected Madin-Darby canine kidney cells. Co-expression of mouse Ostα-Ostβ, 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 Ostα-Ostβ expression. Co-expression of Ostα and Ostβ was required to convert the Ostα subunit to a mature glycosylated endoglycosidase H-resistant form, suggesting that co-expression facilitates the trafficking of Ostα through the Golgi apparatus. Immunolocalization studies showed that co-expression was necessary for plasma membrane expression of both Ostα and Ostβ. These results demonstrate that the mouse Ostα-Ostβ heteromeric transporter is a basolateral bile acid carrier and may be responsible for bile acid efflux in ileum and other ASBT-expressing tissues.
doi:10.1074/jbc.M412752200
PMCID: PMC1224727  PMID: 15563450

Results 1-4 (4)