Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats

J Biol Chem. 2019 Mar 15;294(11):4272-4281. doi: 10.1074/jbc.RA118.006158. Epub 2019 Jan 16.


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.

Keywords: aldose reductase; fatty acid; fructose; liver metabolism; metabolic syndrome; polyol pathway; sorbitol; uric acid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / metabolism*
  • Aldehyde Reductase / metabolism*
  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Fructose / biosynthesis*
  • Fructose / metabolism
  • Hep G2 Cells
  • Humans
  • Male
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Oxidative Stress / drug effects
  • Polymers / analysis
  • Polymers / metabolism*
  • Rats
  • Rats, Wistar
  • Tumor Cells, Cultured
  • Uric Acid / metabolism
  • Uric Acid / pharmacology*


  • Polymers
  • polyol
  • Uric Acid
  • Fructose
  • Aldehyde Reductase