The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction

Abstract

The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut.

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…FXR stimulation also inhibits contraction of HSCs mediated by endothelin-1 [104]. The novel nonsteroidal FXR agonist PX20606 improves sinusoidal flow and lowers PVP in association with limiting fibrosis, angiogenesis, and endothelial dysfunction in experimental models of PHT [105]. Moreover, treatment of db/db obese mice with INT-767, a dual FXR/TGR5 agonist, results in diminished hepatic steatosis, reduced expression of pro-inflammatory cytokines, and phenotype shift of macrophages toward the anti-inflammatory M2 phenotype [106].…”

Novel treatment options for portal hypertension

“…demonstrated in two different cirrhotic rodent models that treatment with OCA improved PHT by decreasing the intrahepatic vascular tone without deleterious impact on mean arterial pressure or liver biochemistry [175]. Further evidence came by two subsequent rodent studies confirming the anti-portal hypertensive effects of FXR agonism with OCA and PX-20606, respectively [176,177]. The underlying molecular mechanisms involved affect (i) NO metabolism, (ii) H 2 S production, (iii) hepatic inflammation and (iv) bacterial translocation:

Asymmetric dimethylarginine is a circulating eNOS inhibitor [178] which correlates with HVPG [179] and which is degraded by dimethylarginine dimethylaminohydrolases (DDAH).

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“…In portal hypertensive rats, DDAH isoforms have been shown to be up-regulated by FXR agonists, thus restoring endothelial dysfunction and contributing to the decrease in portal pressure [175–177]. In addition, also eNOS expression and activity were stimulated upon FXR agonism [177]. …”

“…In CCl4 rats, FXR agonists protected against the down-regulation of cystathionase expression and increased the production of vasodilatory H 2 S, which contributed to the decrease in portal pressure [177,180]. …”

Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

“…Also, a signifi cant decrease in hepatic fi brosis and infl ammatory cell infi ltration and cytokines were observed [34]. Recently, a novel, non-steroidal FXR agonist, PX20606, has been shown to have anti-fi brotic and vasodilator properties and lowers portal hypertension [102]. A newly found non-bile steroidal dual ligand for FXR and GPBAR1 receptors, BAR502, reverses high-fat diet induced steatohepatitis in mice by promoting the browning of adipose tissue [103].…”