Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1319-1325. doi: 10.1016/j.bbadis.2017.08.021. Epub 2017 Aug 25.
Bile salts represent signalling molecules with a variety of endocrine functions. Bile salt effects are mediated by different receptor molecules, comprising ligand-activated nuclear transcription factors as well as G protein-coupled membrane-bound receptors. The farnesoid X receptor (FXR) and the plasma membrane-bound G protein-coupled receptor TGR5 (Gpbar-1) are prototypic bile salt receptors of both classes and are highly expressed in the liver including the biliary tree as well as in the intestine. In liver, TGR5 is localized in different non-parenchymal cells such as sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells and small and large cholangiocytes. Through TGR5 bile salts can mediate choleretic, cell-protective as well as proliferative effects in cholangiocytes. A disturbance of these signalling mechanisms can contribute to the development of biliary diseases. In line with the important role of TGR5 for bile salt signalling, TGR5 knockout mice are more susceptible to cholestatic liver damage. Furthermore, in absence of TGR5 cholangiocyte proliferation in response to cholestasis is attenuated and intrahepatic and extrahepatic bile ducts show increased cell damage, underscoring the role of the receptor for biliary physiology. Decreased TGR5 expression may also contribute to the development or progression of cholangiopathies like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) since reduced TGR5-dependent cell-protective mechanisms such as bicarbonate secretion renders cholangiocytes more vulnerable towards bile salt toxicity. Nevertheless, TGR5 overexpression or constant stimulation of the receptor can promote cholangiocyte proliferation leading to cyst growth in polycystic liver disease or even progression of cholangiocarcinoma. Not only the stimulation of TGR5-mediated pathways by suitable TGR5 agonists but also the inhibition of TGR5 signalling by the use of antagonists represent potential therapeutic approaches for different types of biliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
胆汁盐是具有多种内分泌功能的信号分子。胆汁盐的作用是通过不同的受体分子介导的，包括配体激活的核转录因子和 G 蛋白偶联的膜结合受体。法尼醇 X 受体（FXR）和质膜结合的 G 蛋白偶联受体 TGR5（Gpbar-1）是这两类的典型胆汁盐受体，在肝脏中高度表达，包括胆管树以及肠道。在肝脏中，TGR5 定位于不同的非实质细胞，如窦状内皮细胞、枯否细胞、肝星状细胞和小胆管和大胆管细胞。通过 TGR5，胆汁盐可以在胆管细胞中介导胆汁分泌、细胞保护和增殖作用。这些信号机制的紊乱可能导致胆道疾病的发生。与 TGR5 对胆汁盐信号的重要作用一致，TGR5 敲除小鼠对胆汁淤积性肝损伤更敏感。此外，在没有 TGR5 的情况下，胆管细胞对胆汁淤积的增殖反应减弱，肝内和肝外胆管显示出增加的细胞损伤，强调了受体在胆汁生理中的作用。TGR5 表达的降低也可能导致胆管疾病的发生或进展，如原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC），因为减少 TGR5 依赖的细胞保护机制，如碳酸氢盐分泌，使胆管细胞更容易受到胆汁盐毒性的影响。然而，TGR5 的过表达或受体的持续刺激可能会促进胆管细胞增殖，导致多囊肝病中的囊肿生长，甚至进展为胆管癌。不仅合适的 TGR5 激动剂刺激 TGR5 介导的途径，而且使用拮抗剂抑制 TGR5 信号转导，都是治疗不同类型胆道疾病的潜在方法。本文是由 Jesus Banales、Marco Marzioni、Nicholas LaRusso 和 Peter Jansen 编辑的特刊“健康与疾病中的胆管细胞”的一部分。
