Background: Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Results: Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Conclusion: Rather than a consequence, uric acid induces fatty liver Significance: Hyperuricemic people are more prone to develop fructose-induced fatty liver.

The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.

Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high fructose corn syrup (HFCS)) not only increases the risk for NAFLD, but also, nonalcoholic steatohepatitis (NASH). Here we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked with metabolism of fructose by fructokinase C, resulting in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations in gut permeability, microbiome, and associated endotoxemia contributes to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

Hyperuricemia induces arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis, as well as arterial hypertension. These studies provide a potential mechanism by which hyperuricemia can mediate hypertension and renal disease.

We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.

Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.

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.

Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome.