Targeting the transsulfuration-H₂S pathway by FXR and GPBAR1 ligands in the treatment of portal hypertension

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• 作者：Stefano Fiorucci ; MD^a ; ^{stefano.fiorucci@unipg.it" class="auth_mail" title="E-mail the corresponding author} ; Eleonora Distrutti ; MD^b ; ^{eleonoradistrutti@katamail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cirrhosis ; Portal hypertension ; Nitric oxide (NO) ; Hydrogen sulfide (H2S) ; Farnesoid X receptor (FXR) ; G protein bile acid receptor 1 (GPBAR1)
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：111
• 期：Complete
• 页码：749-756
• 全文大小：1360 K

文摘

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.