Obeticholic Acid (INT-747; 6-ECDCA; 6-Ethylchenodeoxycholic acid) is a potent, selective and orally active farnesoid X receptor(FXR) agonist with an EC50 of 99nM[1]. FXR is a ligand-dependent transcription factor belonging to the nuclear hormone receptor superfamily that plays an important role in bile acid, lipid metabolism, carbohydrate homeostasis and inflammatory response[2]. Obeticholic Acid is a semisynthetic hydrophobic bile acid analog used to treat primary biliary cholangitis(PBC) and non-alcoholic steatohepatitis(NASH)[3].
In vitro, treatment of HepG2, Huh7 and SNU-449 cells with Obeticholic Acid (0.01-100µM) for 72h significantly inhibited cell proliferation with IC50 values of 1.067μM, 1.038μM and 0.706μM, respectively, and also inhibited cell migration and invasion[4]. Treatment of primary cultures of human intrahepatic cholangiocarcinoma(iCCA) with Obeticholic Acid (0-2.5µM) for 3-10 days significantly inhibited the proliferation of mucinous and mixed iCCA cells and upregulated FXR gene expression[5].
In vivo, oral treatment of mice with NASH with Obeticholic Acid (10mg/kg) for 4 or 8 weeks significantly inhibited the number of hepatic coronary structures(hCLS), reduced the area of fibrosis and the mRNA expression of fibrotic genes, and long-term treatment had no effect on the body weight and adipose tissue weight of mice[6]. Oral treatment of rats with ascites cirrhosis with Obeticholic Acid (5mg/kg) for 2 weeks significantly reduced intestinal bacterial translocation, reduced intestinal immune cell infiltration, and normalized the expression of inflammatory cytokines[7].
References:
[1] Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity[J]. Journal of medicinal chemistry, 2002, 45(17): 3569-3572.
[2] Shaik F B, Prasad D V R, Narala V R. Role of farnesoid X receptor in inflammation and resolution[J]. Inflammation Research, 2015, 64: 9-20.
[3] Chapman R W, Lynch K D. Obeticholic acid—a new therapy in PBC and NASH[J]. British medical bulletin, 2020, 133(1): 95-104.
[4] Attia Y M, Tawfiq R A, Ali A A, et al. The FXR agonist, obeticholic acid, suppresses HCC proliferation & metastasis: role of IL-6/STAT3 signalling pathway[J]. Scientific reports, 2017, 7(1): 12502.
[5] Di Matteo S, Nevi L, Costantini D, et al. The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma[J]. PLoS One, 2019, 14(1): e0210077.
[6] Goto T, Itoh M, Suganami T, et al. Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis[J]. Scientific reports, 2018, 8(1): 8157.
[7] Úbeda M, Lario M, Muñoz L, et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats[J]. Journal of hepatology, 2016, 64(5): 1049-1057.
Obeticholic Acid（奥贝胆酸；INT-747；6-ECDCA；6-Ethylchenodeoxycholic acid）是一种有效的，选择性的和口服活性的法尼醇X受体（FXR ）激动剂，EC50为99nM[1]。FXR是一种配体依赖性转录因子，属于核激素受体超家族，在胆汁酸、脂质代谢、碳水化合物稳态和炎症反应中发挥重要作用[2]。Obeticholic Acid是一种半合成疏水性胆汁酸类似物，用于治疗原发性胆汁性胆管炎（PBC）和非酒精性脂肪性肝炎（NASH）[3]。
在体外，Obeticholic Acid（0.01-100µM）处理肝癌细胞HepG2、Huh7和SNU-449细胞72h，显著抑制了细胞增殖，IC50值分别为1.067μM、1.038μM和0.706μM，还抑制了细胞迁移和侵袭[4]。Obeticholic Acid（0-2.5µM）处理人肝内胆管癌（iCCA）的原代培养物3-10d，显著抑制了粘液性和混合iCCA细胞的增殖，上调了FXR基因表达[5]。
在体内，Obeticholic Acid（10mg/kg）通过口服治疗NASH小鼠4周或8周，显著抑制了肝冠状结构（hCLS）的数量，减少纤维化面积和纤维化基因的mRNA表达，且长期治疗对小鼠的体重和脂肪组织重量没有影响[6]。Obeticholic Acid（5mg/kg）通过口服治疗腹水性肝硬化大鼠2周，显著减少了肠道细菌易位，减少肠道免疫细胞浸润，使炎性细胞因子表达正常化[7]。