Uric Acid Activates Aldose Reductase and the Polyol Pathway for Endogenous Fructose Production and Fat Accumulation in the Development of Fatty Liver

Abstract

Dietary sugars containing fructose have been strongly associated with the development of fatty liver, but recent studies also suggest fructose can be produced in the liver via the polyol pathway where it may also induce hepatic fat accumulation. Here we investigate 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 was associated with endogenous fructose production and fat accumulation. Uric acid dose stimulated the expression of aldose reductase in HepG2 cells in association with endogenous fructose production and triglyceride accumulation. The mechanism was mediated by uric acid‐induced oxidative stress with the stimulation of the transcription factor NFAT5. Uric acid could amplify the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats also showed elevated hepatic aldose reductase expression, endogenous fructose accumulation and fat accumulation that was significantly reduced by co‐administration of the xanthine oxidase inhibitor, allopurinol. These studies suggest that uric acid, which is generated during fructose metabolism, may act as a positive feedback to stimulate endogenous fructose production by stimulating aldose reductase in the polyol pathway. These studies provide an amplifying mechanism by which soft drinks rich in glucose and fructose can induce non‐alcoholic fatty liver disease.Support or Funding InformationSupported by NIH Grant R01 DK108859This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.