Dietary,
fructose-containing
sugars have been strongly associated with the development of
nonalcoholic fatty liver disease (
NAFLD). Recent studies suggest that
fructose also can be produced via the
polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover,
fructose metabolism yields
uric acid, which is highly associated with
NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether
uric acid regulates
aldose reductase, a key
enzyme in the
polyol pathway. We evaluated whether soluble
uric acid regulates
aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous
fructose production and fat accumulation.
Uric acid dose-dependently stimulated
aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous
fructose production and
triglyceride accumulation. This stimulatory mechanism was mediated by
uric acid-induced oxidative stress and stimulation of the
transcription factor nuclear factor of activated T cells 5 (NFAT5).
Uric acid also amplified the effects of elevated
glucose levels to stimulate hepatocyte
triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic
aldose reductase expression, endogenous
fructose accumulation, and fat buildup that was significantly reduced by co-administration of the
xanthine oxidase inhibitor
allopurinol. These results suggest that
uric acid generated during
fructose metabolism may act as a positive feedback mechanism that stimulates endogenous
fructose production by stimulating
aldose reductase in the
polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in
glucose and
fructose can induce
NAFLD.