Ðanić Maja, Stanimirov Bojan, Pavlović Nebojša, Goločorbin-Kon Svetlana, Al-Salami Hani, Stankov Karmen, Mikov Momir
Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Front Pharmacol. 2018 Dec 3;9:1382. doi: 10.3389/fphar.2018.01382. eCollection 2018.
Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.
除了胆汁酸在小肠中对亲脂性营养物质和药物的消化及增溶作用这一广为人知的功能外，过去二十年中不断涌现的证据表明，胆汁酸作为信号传导和内分泌分子，通过复杂且相互交织的途径调节葡萄糖、脂质和能量代谢，这些途径主要由核受体法尼酯X受体（FXR）和细胞表面G蛋白偶联受体1（TGR5，也称为GPBAR1）的激活介导。胆汁酸与肠道微生物群的相互作用导致循环和肠道胆汁酸池的组成改变、肠道微生物群组成变化以及信号传导途径改变，进一步增加了这些类固醇衍生物生物学功能的复杂性。因此，胆汁酸信号传导途径已成为治疗各种代谢疾病和代谢综合征的有吸引力的靶点，为其治疗开辟了新的潜在途径。此外，人们正在大力揭示胆汁酸与特定受体的内在效力和选择性相关的一些特定特性，并设计具有改善药代动力学和药效学特征的这些受体的新型调节剂。这导致合成了几种半合成胆汁酸衍生物，如6α-乙基鹅去氧胆酸（奥贝胆酸，OCA）、去甲熊去氧胆酸（norUDCA）和12-单酮胆酸（12-MKC），已证明它们在代谢和肝胆疾病中具有积极作用。本综述概述了目前有关胆汁酸在葡萄糖、脂质和能量代谢中的作用的知识，以及胆汁酸在代谢综合征治疗中的潜在应用和未来展望。
