Abstract
Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver.
Highlights
Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are increasing throughout the world [1,2]
Incubation of human hepatocytes with uric acid resulted in KHK protein over-expression in a dose dependent manner which was prevented by addition of the organic anion transport inhibitor, probenecid
We found that KHK is a target gene of the transcription factor associated with carbohydrate metabolism, ChREBP, and that allopurinol could block ChREBP nuclear translocation and activation
Summary
Type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are increasing throughout the world [1,2]. The current epidemics of these conditions have been linked to the increased intake in the last decades of added sugars (primarily in the form of sucrose and high fructose corn syrup, HFCS). A major component of added sugars is fructose, which constitutes 50% of the content of sucrose, and 55% of the most common form of HFCS. The mechanism whereby fructose induces fatty liver appears to be independent of total energy intake. One common finding in clinical studies is that the effect of fructose to induce fatty liver and hypertriglyceridemia varies significantly between humans [6,7,8] while the mechanism accounting for these differences in sensitivity to the effects of fructose remains unknown
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