Reich Maria, Klindt Caroline, Deutschmann Kathleen, Spomer Lina, Häussinger Dieter, Keitel Verena
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Dig Dis. 2017;35(3):235-240. doi: 10.1159/000450917. Epub 2017 Mar 1.
TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling. Key Messages: TGR5 exerts anti-inflammatory effects, protects cholangiocytes from BA-induced toxicity, promotes cholangiocyte secretion and proliferation and reduces portal perfusion pressure. Furthermore, TGR5 mediates gallbladder filling. TGR5 knockout mice have a smaller BA pool size with altered composition and develop more severe liver injury after BA feeding, common bile duct ligation or injection of lipopolysaccharide. The absence of TGR5 also reduces the proliferative and regenerative capacity after partial hepatectomy or liver damage. Stimulation of TGR5 signalling can improve steatohepatitis, portal hypertension and hepatic inflammation in rodent models of liver damage. However, TGR5 activation also promotes the proliferation of cystic and malignant-transformed cholangiocytes.
TGR5 plays an important role in the protection of the liver from BA toxicity under cholestatic conditions. Stimulation of the receptor prevents excessive liver damage in rodent models of cholestasis, steatohepatitis, liver fibrosis and inflammation and also promotes liver regeneration. However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma. Depending on the type of liver disease stimulation as well as inhibition of TGR5, signalling may present a useful therapeutic approach.
TGR5（G蛋白偶联胆汁酸受体1，M-Bar）是一种G蛋白偶联细胞表面受体，对胆汁酸（BA）和不同的类固醇激素有反应。TGR5 mRNA在人和啮齿动物组织中几乎普遍存在，在胆囊、肝脏和肠道中表达非常高。在肝脏中，TGR5存在于窦状内皮细胞、库普弗细胞和胆管细胞中。TGR5的激活会引发细胞内环磷酸腺苷（cAMP）的升高以及进一步的下游信号传导。
TGR5具有抗炎作用，保护胆管细胞免受BA诱导的毒性，促进胆管细胞分泌和增殖，并降低门静脉灌注压力。此外，TGR5介导胆囊充盈。TGR5基因敲除小鼠的BA池大小较小，组成改变，在给予BA、胆总管结扎或注射脂多糖后发生更严重的肝损伤。TGR5的缺失还会降低部分肝切除或肝损伤后的增殖和再生能力。在肝脏损伤的啮齿动物模型中，刺激TGR5信号传导可改善脂肪性肝炎、门静脉高压和肝脏炎症。然而，TGR5激活也会促进囊性和恶性转化胆管细胞的增殖。
TGR5在胆汁淤积条件下保护肝脏免受BA毒性方面发挥重要作用。刺激该受体可防止在胆汁淤积、脂肪性肝炎、肝纤维化和炎症的啮齿动物模型中发生过度的肝损伤，还可促进肝脏再生。然而，TGR5依赖性信号传导的激活也可能触发囊性胆管细胞和恶性转化胆管细胞的增殖和抗凋亡，从而促进多囊肝病中的囊肿生长或胆管癌的进展。根据肝病的类型，刺激以及抑制TGR5信号传导可能是一种有用的治疗方法。
