The role of WNT/β-catenin signaling pathway and glutamine metabolism in the pathogenesis of CCl4-induced liver fibrosis: Repositioning of niclosamide and concerns about lithium

Abstract

BackgroundLiver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma. ObjectiveThe present study aimed to investigate the role of Wnt/β-catenin signaling pathway and glutamine aminohydrolase enzyme (l-glutaminase) in the pathogenesis of liver fibrosis and the potential benefits of niclosamide in treating liver fibrosis. MethodsNinety male Albino rats were divided into 6 equal groups (n = 15) as follows: a normal control group (NC), CCl4-only treated group (Fib.) which received 1 mg/kg CCl4 two times weekly, niclosamide-treated group (Niclo.) which received 5 mg/kg of niclosamide one time daily, lithium chloride-treated group (LiCl) which received 100 mg/kg of LiCl one time daily, niclosamide-and-CCl4-treated group (Niclo. + Fib.) which received same doses of niclosamide and CCl4 given to other groups, and finally lithium chloride-and-CCl4-treated rat group (LiCl + Fib.) which received same doses of LiCl and CCl4 given to other groups. All treatments were administered orally for 8 weeks. Liver tissue was assessed for l-hydroxyproline, beta-catenin (β-catenin), l-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-β1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin α-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured. ResultsThe group of niclosamide-and-CCl4-treated rats showed a significant decrease in total bilirubin, ALT and AST, β-catenin, l-hydroxyproline, l-glutaminase activity, and gene expression of TGF-β1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild α-SMA reactivity compared with the rats treated with CCl4 only (fibrosis group). On the other hand, lithium chloride-and-CCl4-treated rats showed a significant increase in liver indices, TGF-β1 expression, β-catenin, l-hydroxyproline, and l-glutaminase activity with severe α-SMA reactivity and apoptosis in the liver tissue. ConclusionsNiclosamide protected rats against liver fibrosis by inhibiting the Wnt/β-catenin pathway and glutaminolysis.