Original Articles
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. May 7, 2009; 15(17): 2097-2108
Published online May 7, 2009. doi: 10.3748/wjg.15.2097
Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation
Barbara Renga, Andrea Mencarelli, Marco Migliorati, Eleonora Distrutti, Stefano Fiorucci
Barbara Renga, Andrea Mencarelli, Marco Migliorati, Stefano Fiorucci, Department of Clinical and Experimental Medicine, University of Perugia, Via E dal Pozzo, 06122 Perugia, Italy
Eleonora Distrutti, Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, 06122 Perugia, Italy
Author contributions: Renga B designed the study, carried out in vitro experiments and wrote the manuscript; Migliorati M performed in vitro experiments (Western blotting and PCR); Mencarelli A performed in vivo experiments; Distrutti E was involved in designing and writing the manuscript; Fiorucci S designed the study and wrote the manuscript.
Correspondence to: Barbara Renga, Department of Clinical and Experimental Medicine University of Perugia, Via E dal Pozzo, 06122 Perugia, Italy. barbara.renga@unipg.it
Telephone: +39-075-5855819   
Fax: +39-075-5855819
Received: December 19, 2008
Revised: March 20, 2009
Accepted: March 27, 2009
Published online: May 7, 2009

AIM: To investigate whether the farnesoid X receptor (FXR) regulates expression of liver cystathionase (CSE), a gene involved in hydrogen sulfide (H2S) generation.

METHODS: The regulation of CSE expression in response to FXR ligands was evaluated in HepG2 cells and in wild-type and FXR null mice treated with 6-ethyl chenodeoxycholic acid (6E-CDCA), a synthetic FXR ligand. The analysis demonstrated an FXR responsive element in the 5’-flanking region of the human CSE gene. The function of this site was investigated by luciferase reporter assays, chromatin immunoprecipitation and electrophoretic mobility shift assays. Livers obtained from rats treated with carbon tetrachloride alone, or in combination with 6-ethyl chenodeoxycholic acid, were studied for hydrogen sulphide generation and portal pressure measurement.

RESULTS: Liver expression of CSE is regulated by bile acids by means of an FXR-mediated mechanism. Western blotting, qualitative and quantitative polymerase chain reaction, as well as immunohistochemical analysis, showed that expression of CSE in HepG2 cells and in mice is induced by treatment with an FXR ligand. Administration of 6E-CDCA to carbon tetrachloride treated rats protected against the down-regulation of CSE expression, increased H2S generation, reduced portal pressure and attenuated the endothelial dysfunction of isolated and perfused cirrhotic rat livers.

CONCLUSION: These results demonstrate that CSE is an FXR-regulated gene and provide a new molecular explanation for the pathophysiology of portal hypertension.

Keywords: Nuclear receptor, Farnesoid X receptor, Cystathionase, Hydrogen sulfide, Portal hypertension