A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

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Xiao Y, Wang Y, Liu Y, Wang W, Tian X, Chen S, Lu Y, Du J, Cai W

A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

Liver Int. 2021 Sep;41(9):2117-2131. doi: 10.1111/liv.14906. Epub 2021 May 18.

PubMed ID

33894097 [ View in PubMed

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Abstract

BACKGROUND & AIMS: Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL). METHODS: The piglets received BDL and TXR for 2 wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7alpha-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL. CONCLUSION: TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tropifexor	Bile acid receptor	Protein	Humans	Unknown	Agonist Binder	Details