Metabolomic study of the improvement of nitazoxanide on Western-diet induced hepatic steatosis in ApoE-/-mice
Nitazoxanide is an FDA-approved antiprotozoal drug.Our previous study found that oral administration of nitazoxanide inhibited Western diet(WD)-induced hepatic steatosis in ApoE-/-mice.However,the specific mechanism remains to be elucidated.In the present study,we performed an untargeted metabolomics approach to reveal the effect of nitazoxanide on the liver metabolic profiles in WD-fed ApoE-/-mice,and carried out the cellular experiments to elucidate the underlying mechanisms.UPLC-MS-based untargeted metabolomics analysis was used to investigate the effect of nitazoxanide on global metabolite changes in liver tissues.The differential metabolites were screened for enrichment analysis and pathway analysis.Hepatocytes were treated with tizoxanide,the metabolite of nitazoxanide,to investigate the underlying mechanism based on the findings in metabolomics study.The improvement of liver lipid metabolism disorders by nitazoxanide treatment in WD-fed ApoE-/-mice was mainly through regulating glycerophospholipid metabolism,D-glutamine and glutamate metabolism,glutathione metabolism,and arginine biosynthesis metabolism.Tizoxanide,the active metabolite of nitazoxanide,increased glutathione(GSH)contents and glutamate-cysteine ligase catalytic subunit(Gcl-c)and glutathione reductase(Gsr)mRNA expressions in HepG2 cells.Tizoxanide increased cystathionine β-synthase(CBS)and phosphatidylethanolamine N-methyltransferase(PEMT)protein levels,inhibited lipid accumulation in hepatocytes induced by free fatty acid(FFA).Tizoxanide increased S-adenosyl-L-homocysteine hydrolase(SAHH)protein levels in HepG2 cells and mouse primary liver cells stimulated with free fatty acid(FFA).Tizoxanide increased N-acetyl glutamate synthase(Nags)and carbamoylphosphate synthetase 1(Cps1)mRNA expressions in HepG2 cells.In conclusion,nitazoxanide improves WD-induced hepatic steatosis in ApoE-/-mice and the underlying mechanisms include increasing CBS expression,GSH content,PEMT protein expression,Nags and Cps1 mRNA expression in hepatocytes.
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