Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats

Abstract

The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-ductligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rhokinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2. Conclusion: FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis. (HEPATOLOGY 2014;59:2286-2298 See Editorial on Page 2072 P ortal hypertension (PHT) is the driving force behind many of the lethal complications of cirrhosis, such as gastroesophageal variceal bleeding, hepatic encephalopathy, ascites, hepatorenal syndrome, and bacterial infections. [1][2][3][4] Despite its effect on morbidity and mortality, current pharmacotherapy remains almost exclusively restricted to the use of nonselective beta-adrenergic blockers. These drugs indisputably lower PHT by decreasing portal inflow, 5-9 but are

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…FXR increases the expression of dimethylarginine dimethylaminohydrolase (DDAH), which eliminates asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of endothelial nitric oxide synthase (eNOS) abundant in cirrhosis [102]. Obeticholic acid (OCA), a synthetic bile acid ligand of FXR, reduces experimental PHT by reactivating FXR signaling pathways of vasorelaxation through DDAH and eNOS upregulation and Rho-kinase repression [103]. FXR stimulation also inhibits contraction of HSCs mediated by endothelin-1 [104].…”

Obeticholic acid: A new light in the shadows treating portal hypertension?

“…4 FXR, a bile-acid-responsive transcription factor expressed in the liver, orchestrates a multiplicity of signaling pathways, including those related to bile acid homeostasis, carbohydrates and lipids metabolism, and vasoactive systems, among others. [5][6][7] In addition, it has been suggested, although controversial, that FXR modulates liver fibrosis.…”

Cirrhotic Portal Hypertension: New Insights in an Old Syndrome

“…The scientific interest related to the functional component of IHVR, which seems to be target of future pharmacological interventions, has grown and become more attractive. This augmented IHVR derives from already discussed complex mechanisms ( VERBEKE;FARRE et al, 2014). Drugs with an anti-oxidative stress effect, such as ascorbic acid -Vitamin C -are potent natural antioxidants that are found lacking in hepatic cirrhosis ( VERBEKE;FARRE et al, 2014).…”

“…This augmented IHVR derives from already discussed complex mechanisms ( VERBEKE;FARRE et al, 2014). Drugs with an anti-oxidative stress effect, such as ascorbic acid -Vitamin C -are potent natural antioxidants that are found lacking in hepatic cirrhosis ( VERBEKE;FARRE et al, 2014). Tetrahydrobiopterin, responsible cofactor to regulate eNOS activity, is capable of increasing availability of ON and is found diminished in in hepatic cirrhosis and studies with supplementation have already been done with optimistic results (MATEI; RODRIGUEZ-VILARRUPLA ET AL., 2006; MATEI; RODRIGUEZ-VILARRUPLA et al, 2008).…”

“…Verbeker and collaborators have shown that in models of hepatic cirrhosis in rats, there is a deficiency of FXR and its restoration improves PH decreasing RVIH without important deleterious hemodynamic effects ( VERBEKE;FARRE et al, 2014).…”