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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis

Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale Università degli Studi di Perugia, Perugia, Italy (S.F., C.C., E.A., S.O., G.S., G.R. D.C., A.M.); Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina (B.G., T.M.W.); Intercept Pharmaceuticals, New York, New York (M.P.); and Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Perugia, Italy (B.M.S., R.P.)

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17-ethynylestradiol (E₂17) to rats. The exposure of rat hepatocytes to 1 µM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7-hydroxylase (cyp7a1), oxysterol 12-hydroxylase (cyp8b1), and Na⁺/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E₂17. Thus, 6-ECDCA reverted bile flow impairment induced by E₂17, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E₂17 cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Address correspondence to: Dr. Stefano Fiorucci, Gastroenterologia ed Epatologia, Policlinico Monteluce, Via E dal Pozzo, 06111 Perugia, Italy. E-mail: fiorucci{at}unipg.it

This article has been cited by other articles:

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