Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Pharmacol Ther. 2020 Jul;211:107542. doi: 10.1016/j.pharmthera.2020.107542. Epub 2020 Apr 2.
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.
有机溶质转运体 α/β（OSTα/β）是一种异源溶质载体蛋白，可将胆汁酸、类固醇代谢物和药物转运进出细胞。OSTα/β 蛋白在各种组织中表达，但在胃肠道中表达最高，在胃肠道中促进胆汁酸从肠道回流到肝脏。先前的研究表明，OSTα/β 在肝外胆汁淤积、梗阻性胆汁淤积和原发性胆汁性胆管炎（PBC）患者的肝组织中上调，这些病症的特征是肝内和/或全身循环中胆汁酸浓度升高。发现 OSTα/β 在非酒精性脂肪性肝炎（NASH）患者的肝脏中高度上调，这进一步凸显了该转运体的临床相关性，因为随着肥胖症的流行，NASH 的发病率以惊人的速度增长。由于 OSTα/β 与胆汁酸的动态平衡密切相关，并受核受体法尼醇 X 受体的严格调节，因此 OSTα/β 是治疗胆汁淤积性肝病和其他与胆汁酸相关的代谢紊乱（如肥胖和糖尿病）的潜在药物靶点。用于治疗 PBC 的半合成胆汁酸奥贝胆酸正在接受 NASH 治疗的审查，并正在开发用于治疗其他代谢紊乱，诱导 OSTα/β。一些与肝毒性相关的药物抑制 OSTα/β，表明 OSTα/β 可能在药物性肝损伤（DILI）中发挥作用。此外，已报道了由于 OSTα/β 两个亚基的纯合遗传缺陷导致腹泻和胆汁淤积特征的临床病例。本文综述了 OSTα/β 的最新数据，总结了 OSTα/β 的结构-功能和表达-功能关系、该重要转运体的调节、药物和其他化合物与 OSTα/β 的相互作用以及 OSTα/β 与其他溶质载体转运体和三磷酸腺苷结合盒转运体的比较等方面的现有文献。描述和讨论了从基础到更具临床重点的研究工作的结果。
