Inhibition of ۵-Lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model

Objective(s): Arachidonic Acid/۵-lipoxygenase (AA/۵-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/۵-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of ۵-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/۵-LOX pathway including PLA۲ and ۵-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (۱-[۱-(۱-benzothiophen-۲-yl)ethyl]-۱-hydroxyurea) was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/۵-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA۲ and ۵-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/۵-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/۵-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

Keywords:

Arachidonic acid , Lipid metabolism , ۵-Lipoxygenase , Nonalcoholic fatty liver-disease , Proinflammatory mediators , Zileuton