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

Background: Liver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma. Objective: The present study aimed to investigate the role of Wnt/beta-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. Methods: Ninety 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 (beta-catenin), L-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-beta 1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin alpha-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured. Results: The group of niclosamide-and-CCl4-treated rats showed a significant decrease in total bilirubin, ALT and AST, beta-catenin, L-hydroxyproline, L-glutaminase activity, and gene expression of TGF-beta 1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild alpha-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-beta 1 expression, beta-catenin, L-hydroxyproline, and L-glutaminase activity with severe alpha-SMA reactivity and apoptosis in the liver tissue. Conclusions: Niclosamide protected rats against liver fibrosis by inhibiting the Wnt/beta-catenin pathway and glutaminolysis.