S. Fiorucci, S. Cipriani, A. Mencarelli, F. Baldelli, G. Bifulco and A. Zampella Pages 753 - 762 ( 10 )
6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liverrelated metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.
Chenodeoxycholic acid, FXR, MRP4, non alcoholic liver steatosis (NASH), cholestasis, 6-ethyl-chedeoxycholic acid, 6E-CDCA, farnesoid X, agonistic activity, cholestatic liver diseases, biliary cirrhosis, PBC, NAFLD, NASH, bile sensor, bile acid uptake, metabolism, excretion, atherosclerosis, alkaline phosphatase, Treatment, amelioration, LDL
University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facolta di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, 06132 Perugia, Italy.