Role of the Inducible Nitric Oxide Synthase in the Onset of Fructose-Induced Steatosis in Mice

To test the hypothesis that the inducible nitric oxide synthase (iNOS) is involved in mediating the toll-like receptor 4-dependent effects on the liver in the onset of fructose-induced steatosis, wild-type and iNOS knockout (iNOS(-/-)) mice were either fed tap water or 30% fructose solution for 8 weeks. Chronic consumption of 30% fructose solution led to a significant increase in hepatic steatosis and inflammation as well as plasma alanine-aminotransferase levels in wild-type mice. This effect of fructose feeding was markedly attenuated in iNOS (/) mice. Hepatic lipidperoxidation, concentration of phospho-I kappa B, nuclear factor kappa B activity, and tumor necrosis factor-alpha mRNA level were significantly increased in fructose-fed wild-type mice, whereas in livers of fructose-fed iNOS (/) mice, lipidperoxidation, phospho-IkB, nuclear factor kB activity, and tumor necrosis factor-alpha expression were almost at the level of controls. However, portal endotoxin levels and hepatic myeloid differentiation factor 88 expression were significantly higher in both fructose-fed groups compared to controls. Taken together, these data suggest that (i) the formation of reactive oxygen species in liver is a key factor in the onset of fatty liver and (ii) iNOS is involved in mediating the endotoxin/toll-like receptor 4-dependent effects in the development of fructose-induced fatty liver. Antioxid. Redox Signal. 14, 2121-2135.