Allopurinol potentiates the hepatoprotective effect of metformin and vitamin E in fructose-induced fatty liver in rats.

Non-alcoholic fatty liver disease (NAFLD) is a challenging health problem. Hyperuricemia is a key player in the pathogenesis of NAFLD. This study investigated the effect of allopurinol (uric acid synthesis inhibitor) in combination with metformin and vitamin E in prevention of fructose induced-fatty liver in rats. Rats were divided into 7 groups: control group, fructose group (model group of NAFLD), allopurinol-treated group, metformin-treated group, vitamin E-treated group, metformin plus vitamin E-treated group and a combination group (received allopurinol plus metformin plus vitamin E). Development of NAFLD was assessed biochemically by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as by histopathological examination. Oxidative stress parameters [reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA)], and the inflammatory mediators tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) were assessed, along with serum levels of uric acid and triglyceride (TG). Combination of allopurinol plus metformin plus vitamin E significantly attenuated fatty changes compared to their respective monotherapy. Interestingly, though all treated groups showed significant attenuation in the oxidative stress markers, TNF-α level and iNOS immunostaining in hepatic tissue, along with a significant decrease in the levels of uric acid and TG, the combination group showed a further significant decrease in the serum level of uric acid and iNOS immunostaining compared to other treated regimens. Allopurinol synergistically increases the protective effect of metformin and vitamin E in treatment of NAFLD, namely via reduction of uric acid synthesis and iNOS expression.