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Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside.

ABSTRACT: Organic solute transporter alpha/beta (OSTα/β) is a heteromeric solute carrier protein that transports bile acids, steroid metabolites and drugs into and out of cells. OSTα/β protein is expressed in various tissues, but its expression is highest in the gastrointestinal tract where it facilitates the recirculation of bile acids from the gut to the liver. Previous studies established that OSTα/β is upregulated in liver tissue of patients with extrahepatic cholestasis, obstructive cholestasis, and primary biliary cholangitis (PBC), conditions that are characterized by elevated bile acid concentrations in the liver and/or systemic circulation. The discovery that OSTα/β is highly upregulated in the liver of patients with nonalcoholic steatohepatitis (NASH) further highlights the clinical relevance of this transporter because the incidence of NASH is increasing at an alarming rate with the obesity epidemic. Since OSTα/β is closely linked to the homeostasis of bile acids, and tightly regulated by the nuclear receptor farnesoid X receptor, OSTα/β is a potential drug target for treatment of cholestatic liver disease, and other bile acid-related metabolic disorders such as obesity and diabetes. Obeticholic acid, a semi-synthetic bile acid used to treat PBC, under review for the treatment of NASH, and in development for the treatment of other metabolic disorders, induces OSTα/β. Some drugs associated with hepatotoxicity inhibit OSTα/β, suggesting a possible role for OSTα/β in drug-induced liver injury (DILI). Furthermore, clinical cases of homozygous genetic defects in both OSTα/β subunits resulting in diarrhea and features of cholestasis have been reported. This review article has been compiled to comprehensively summarize the recent data emerging on OSTα/β, recapitulating the available literature on the structure-function and expression-function relationships of OSTα/β, the regulation of this important transporter, the interaction of drugs and other compounds with OSTα/β, and the comparison of OSTα/β with other solute carrier transporters as well as adenosine triphosphate-binding cassette transporters. Findings from basic to more clinically focused research efforts are described and discussed.

SUBMITTER: Beaudoin JJ

PROVIDER: S-EPMC7480074 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5 µM) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 µM, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 µM, respectively, for glycochenodeoxycholate; 140, 265, and 527 µM, respectively, for taurocholate; 59.8, 102, and 117 µM, respectively, for glycocholate. The potential role of OSTα/β in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 µM) resulted in substantial OSTα/β induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.

Project description:SLC39A8 is an evolutionarily highly conserved gene that encodes the ZIP8 metal cation transporter in all vertebrates. SLC39A8 is ubiquitously expressed, including pluripotent embryonic stem cells; SLC39A8 expression occurs in every cell type examined. Uptake of ZIP8-mediated Mn2+, Zn2+, Fe2+, Se4+, and Co2+ represents endogenous functions-moving these cations into the cell. By way of mouse genetic differences, the phenotype of "subcutaneous cadmium-induced testicular necrosis" was assigned to the Cdm locus in the 1970s. This led to identification of the mouse Slc39a8 gene, its most closely related Slc39a14 gene, and creation of Slc39a8-overexpressing, Slc39a8(neo/neo) knockdown, and cell type-specific conditional knockout mouse lines; the Slc39a8(-/-) global knockout mouse is early-embryolethal. Slc39a8(neo/neo) hypomorphs die between gestational day 16.5 and postnatal day 1-exhibiting severe anemia, dysregulated hematopoiesis, hypoplastic spleen, dysorganogenesis, stunted growth, and hypomorphic limbs. Not surprisingly, genome-wide association studies subsequently revealed human SLC39A8-deficiency variants exhibiting striking pleiotropy-defects correlated with clinical disorders in virtually every organ, tissue, and cell-type: numerous developmental and congenital disorders, the immune system, cardiovascular system, kidney, lung, liver, coagulation system, central nervous system, musculoskeletal system, eye, and gastrointestinal tract. Traits with which SLC39A8-deficiency variants are currently associated include Mn2+-deficient hypoglycosylation; numerous birth defects; Leigh syndrome-like mitochondrial redox deficiency; decreased serum high-density lipoprotein-cholesterol levels; increased body mass index; greater risk of coronary artery disease, hypotension, cardiovascular death, allergy, ischemic stroke, schizophrenia, Parkinson disease, inflammatory bowel disease, Crohn disease, myopia, and adolescent idiopathic scoliosis; systemic lupus erythematosus with primary Sjögren syndrome; decreased height; and inadvertent participation in the inflammatory progression of osteoarthritis.

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Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside.

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