Farnesoid X receptor regulates cystathionase

May 13, 2009

The expression and activity of Cystathionase is reduced in rodent models of liver injury, leading to hyper-homocysteinemia and impaired generation of hydrogen sulphide, two factors that contribute to endothelial dysfunction and increased intrahepatic resistance.

In the present study the analysis of the human Cystathionase gene promoter demonstrates the presence of an inverted repeat sequence. Administration of an FXR ligand to carbon tetrachloride treated mice protected against down-regulation of Cystathionase expression, increased generation, reduced portal pressure and attenuated the endothelial dysfunction of isolated and perfused livers.

A research article to be published on May 7, 2009 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Barbara Renga and her colleagues in the University of Perugia, Italy used luciferase transfection assay, Electrophoretic Mobility Shift Assay (EMSA), Chromatin Immunoprecipitation Assay and Real-Time PCR to confirm the role of FXR in the regulation of CSE transcription.

The molecular mechanism of the CSE activation by FXR was revealed by identifying a sequence in the 5' flanking region of CSE gene containing a potential IR1 binding site. Co-transfection of HepG2 cells with luciferase reporter vector containing four copies of this putative IR1 resulted in transactivation of the CSE promoter in presence of an FXR ligand, while the mutation of the IR1 binding site abrogates this response. The functionality of this IR1 site was also confirmed by EMSA and CHIP assay.

In the normal liver the CSE expression was significantly increased when mice were fed a chow diet supplemented with 5 mg/kg body weight of 6E-CDCA while the FXR ligand failed to up-regulate CSE mRNA expression in FXR knock-out mice.

Contraction of presinusoidal myofibroblasts has relevance in regulating intrahepatic resistance and short term administration of 6E-CDCA regulates CSE expression in normal mice, therefore the authors have investigated whether acute administration of an FXR ligand effectively modulates CSE expression in CCl4 treated mice. The author demonstrated that CSE liver expression was down-regulated in an animal model of liver damage induced by CCl4 and that treatment with 6E-CDCA resulted in a robust induction of CSE expression only in FXR +/+ mice

The reduction of CSE expression in the cirrhotic liver contributes to the development of increased intrahepatic resistance and portal hypertension. The authors therefore investigated whether in vivo administration of an FXR ligand modulates hepatic resistance in cirrhotic rats.

In conclusion, they have shown that CSE is an FXR-regulated gene. By linking the deficiency of CSE to the FXR activity the present study provides a new molecular explanation to the pathophysiology of portal hypertension. It also proposes the concept that FXR agonists might correct for the altered generation of endogenous hepatic vasodilators that takes place in chronic liver diseases.

More information: Renga B, Mencarelli A, Migliorati M, Distrutti E, Fiorucci S. Bile-acid-activated farnesoid X receptor regulates hydrogen sulfide production and hepatic microcirculation. World J Gastroenterol 2009; 15(17): 2097-2108 www.wjgnet.com/1007-9327/15/2097.asp

Source: (news : web)

Explore further: US scientists make embryonic stem cells from adult skin

add to favorites email to friend print save as pdf

Related Stories

If your systolic stinks, 'rotten egg' gas may be why

Oct 23, 2008

Anyone with a nose knows the rotten-egg odor of hydrogen sulfide, a gas generated by bacteria living in the human colon. Now an international team of scientists has discovered that cells inside the blood vessels of mice ...

Cathepsin B increases apoptosis in fulminant hepatic failure

Mar 20, 2009

The traditional view is that hepatocyte necrosis is the main feature of fulminant hepatic failure, but increasing evidence implicates a dominant role for hepatocyte apoptosis in this pathogenesis. It is not known if cathepsin ...

Researchers find a new role for a 'Foxy Old Gene'

Aug 01, 2008

Researchers at the University of Pennsylvania School of Medicine have discovered that a protein called FOXA2 controls genes that maintain the proper level of bile in the liver. FOXA2 may become the focus for ...

Too much sperm may kill the queen

Jun 16, 2006

Researchers at CSE (Centre for Social Evolution) at the Institute of Biology, University of Copenhagen have studied the sperm-quality among ants.

Recommended for you

Leeches help save woman's ear after pit bull mauling

Apr 18, 2014

(HealthDay)—A pit bull attack in July 2013 left a 19-year-old woman with her left ear ripped from her head, leaving an open wound. After preserving the ear, the surgical team started with a reconnection ...

New pain relief targets discovered

Apr 17, 2014

Scientists have identified new pain relief targets that could be used to provide relief from chemotherapy-induced pain. BBSRC-funded researchers at King's College London made the discovery when researching ...

User comments : 0

More news stories

Cancer stem cells linked to drug resistance

Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego School of Medicine have discovered ...

Making graphene in your kitchen

Graphene has been touted as a wonder material—the world's thinnest substance, but super-strong. Now scientists say it is so easy to make you could produce some in your kitchen.