title: Targeting the transsulfuration-H2S pathway by FXR and GPBAR1 ligands in the treatment of portal hypertension.
abstract: Cirrhosis is a end-stage disease of the liver in which fibrogenesis, angiogenesis and distortion of intrahepatic microcirculation lead to increased intrahepatic resistance to portal blood flow, a condition known as portal hypertension. Portal hypertension is maintained by a variety of molecular mechanisms including sinusoidal endothelial cells (LSECs) hyporeactivity, activation of hepatic stellate cells (HSCs), reduction in hepatic endothelial nitric oxide synthase (eNOS) activity along with increased eNOS-derived NO generation in the splanchnic and systemic circulations. A reduction of the expression/function of the two major hydrogen sulfide (H2S)-producing enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), has also been demonstrated. A deficit in the transsulfuration pathway leading to the accumulation of homocysteine might contribute to defective generation of H2S and endothelial hyporeactivity. Bile acids are ligands for nuclear receptors, such as farnesoid X receptor (FXR), and G-protein-coupled receptors (GPCRs), such as the G-protein bile acid receptor 1 (GPBAR1). FXR and GPBAR1 ligands regulate the expression/activity of CSE by both genomic and non-genomic effects and have been proved effective in protecting against endothelial dysfunction observed in rodent models of cirrhosis. GPBAR1, a receptor for secondary bile acids, is selectively expressed by LSECs and its activation increases the expression of CSE and attenuates the production of endotelin-1, a potent vasoconstrictor agent. In vivo GPBAR1 ligand attenuates the imbalance between vasodilatory and vaso-constricting agents, making GPBAR1 a promising target in the treatment of portal hypertension.
authors.affiliation: Department of Surgical and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132, Perugia, Italy. Electronic address: stefano.fiorucci@unipg.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: S.C. di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06132, Perugia, Italy. Electronic address: eleonoradistrutti@katamail.com.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000959:Antihypertensive Agents; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide; D008024:Ligands; D009569:Nitric Oxide; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human
keywords: Cirrhosis; Farnesoid X receptor (FXR); G protein bile acid receptor 1 (GPBAR1); Hydrogen sulfide (H(2)S); Nitric oxide (NO); Portal hypertension