Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.
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 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 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 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, 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 E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.
Fiorucci
Stefano
S
Gastroenterologia ed Epatologia, Policlinico Monteluce, Perugia, Italy. fiorucci@unipg.it
Clerici
Carlo
C
Antonelli
Elisabetta
E
Orlandi
Stefano
S
Goodwin
Bryan
B
Sadeghpour
Bahman M
BM
Sabatino
Giuseppe
G
Russo
Giuseppe
G
Castellani
Danilo
D
Willson
Timothy M
TM
Pruzanski
Mark
M
Pellicciari
Roberto
R
Morelli
Antonio
A
D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002779:Cholestasis / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D004967:Estrogens; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid