Abstract
BackgroundGPBAR1 is a bile acids activated receptor expressed in entero-hepatic tissues. In the liver expression of GPBAR1 is restricted to sinusoidal and Kuppfer cells. In the systemic circulation vasodilation caused by GPBAR1 agonists is abrogated by inhibition of cystathione-γ-liase (CSE), an enzyme essential to the generation of hydrogen sulfide (H2S), a vasodilatory agent. Portal BAR501 is a semisynthetic bile acid derivative endowed with a potent and selective agonistic activity toward GPBAR1.MethodsCirrhosis was induced in mice by carbon tetrachloride (CCL4) administration for 9 weeks. Liver endothelial dysfunction was induced by feeding wild type and Gpbar1-/- mice with methionine for 4 weeks. In both models, mice were administered BAR501, 15 mg/kg/day.ResultsBy transactivation assay we demonstrate that BAR501 is a selective GPBAR1 agonist devoid of any FXR agonistic activity. In naïve rats, BAR501 effectively reduced hepatic perfusion pressure and counteracted the vasoconstriction activity of norepinephrine. In the CCl4 model, 9 weeks treatment with BAR501 effectively protected against development of endothelial dysfunction by increasing liver CSE expression and activity and by reducing endothelin (ET)-1 gene expression. In mice feed methionine, treatment with BAR501 attenuated endothelial dysfunction and caused a GPBAR1-dependent regulation of CSE. Using human liver sinusoidal cells, we found that modulation of CSE expression/activity is mediated by both genomic (recruitment of CREB to CRE in the CSE promoter) and non-genomic effects, involving a Akt-dependent phosporylation of CSE and endothelial nitric oxide (NO) synthase (eNOS). BAR501, phosphorylates FOXO1 and inhibits ET-1 transcription in liver sinusoidal cells.ConclusionsBAR501, a UDCA-like GPBAR1 agonist, rescues from endothelial dysfunction in rodent models of portal hypertension by exerting genomic and non-genomic effects on CSE, eNOS and ET-1 in liver sinusoidal cells.
Highlights
Bile acids are amphipatic molecules synthesized in the liver from oxidation of cholesterol
By transactivation assay we demonstrate that BAR501 is a selective GPBAR1 agonist devoid of any FXR agonistic activity
In the CCl4 model, 9 weeks treatment with BAR501 effectively protected against development of endothelial dysfunction by increasing liver CSE expression and activity and by reducing endothelin (ET)-1 gene expression
Summary
Bile acids are amphipatic molecules synthesized in the liver from oxidation of cholesterol. Beside their role in nutrient absorption, primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), and their glycine and taurine conjugates, act as signaling molecules by activating a family of receptors collectively known as the “bile acid activated receptors” (BARs) [1,2,3]. GPBAR1 mediates non-genomic activities of secondary bile acids by increasing intracellular concentrations of cAMP, leading to downstream activation of cAMP-response element (CRE)binding proteins (CREBs) in target cells. The endothelial dysfunction occurring in liver cirrhosis, leads to enhanced contraction of activated perisinusoidal hepatic stellate cells (HSC) and increased intrahepatic vascular resistance to portal flow [4,5,6]. Portal BAR501 is a semisynthetic bile acid derivative endowed with a potent and selective agonistic activity toward GPBAR1
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