Abstract
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.
Highlights
Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD)
NAFLD is an important cause of liver disease and is strongly associated both with intake of sugary beverages (1– 4, 7, 39 – 44) and with hyperuricemia [1, 2, 12,13,14, 45,46,47,48,49,50,51]
Several studies suggest that the fructose component of added sugars may have an important role in mediating fatty liver [4, 42] and that this is mediated in part because of the generation of uric acid that occurs during fructose metabolism [9, 10, 22]
Summary
Nonalcoholic fatty liver disease (NAFLD) has become one of the most important causes of chronic liver disease and cirrhosis. Aldose reductase is minimally expressed in the human liver [17, 18] This has been shown experimentally in WT mice in which hepatic production of fructose is minimal [15, 16]. High-glycemic diets (glucose-enriched), as well as high-salt diets, can induce the expression of AR in the liver of mice, resulting in endogenous fructose production and fructose-dependent development of NAFLD [15, 16]. The importance of this finding is supported by studies showing that inhibition of AR protects type 2 (db db) diabetic mice from developing fatty liver [19]. If uric acid can be shown to regulate fructose production, it provides another key link in understanding why hyperuricemia and sugar intake both appear to be major risk factors for NAFLD
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