Cell lines

Rat hepatocytes

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

24 h

Applications

In rat hepatocytes, obeticholic acid transactivates FXR and modulates FXR regulated genes, resulting in increases of Shp and bsep mRNA expression by 3- to 5-fold and reduction of cyp7a1, cyp8b1, and ntcp mRNA expression by 50 to 70% after exposure to FXR ligands.

Animal models

Male Wistar rats weighing 200-250 g

Dosage form

30 mg/kg

Preparation method

Dissolved in 0.75-1.0 mL of freshly prepared methylcellulose (1%)

Applications

Obeticholic acid can reactivate downstream FXR signaling pathway and reduces PP in the TAA and BDL (thioacetamide (TAA)-intoxicated and bile-duct–ligated) models without systemic hemodynamic impact. It also restores endothelial function and reduces the total IHVR in experimental cirrhosis

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Obeticholic Acid (6alpha-ethyl-chenodeoxycholic acid, 6-ECDCA, INT-747) is a potent and selective agonist of FXR with EC50 value of 99 nM [1].

The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, liver fibrosis, hepatic and intestinal inflammation and cardiovascular disease [2].

Obeticholic Acid is a potent and selective FXR agonist with anticholeretic activity [1]. Obeticholic Acid is a semisynthetic bile acid derivative and potent FXR ligand. In estrogen-induced cholestasis rats, 6-ECDCA protected against cholestasis induced by 17α-ethynylestradiol (E217α) [2]. In cirrhotic portal hypertension (PHT) rat models, INT-747 (30 mg/kg) reactivated the FXR downstream signaling pathway and reduced portal pressure by lowering total intrahepatic vascular resistance (IHVR) without deleterious systemic hypotension. This effect was associated with an increased eNOS activity [3]. In the Dahl rat model of salt-sensitive hypertension and insulin-resistance (IR), high salt (HS) diet significantly increased systemic blood pressure and downregulated tissue DDAH expression. INT-747 enhanced insulin sensitivity and inhibited the decrease of DDAH expression [4].

References:
[1].  Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem, 2002, 45(17): 3569-3572.
[2].  Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther, 2005, 313(2): 604-612.
[3].  Verbeke L, Farre R, Trebicka J, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology, 2014, 59(6): 2286-2298.
[4].  Ghebremariam YT, Yamada K, Lee JC, et al. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One, 2013, 8(4): e60653.