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.

Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

Whether asymptomatic hyperuricemia in the absence of comorbidities increases the risk for cardiometabolic disorders and chronic kidney disease remains controversial. This study was conducted to clarify the association between asymptomatic hyperuricemia and cardiometabolic conditions. Subjects consisted of Japanese adults between 30 and 85 years of age were enrolled in the study at Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, and available at enrollment (2004) and at 5-year follow-up (2009). Subjects were excluded if they were overweight or obese, hypertensive, diabetic, dyslipidemic, had a history of gout or hyperuricemia on medications, or if they had chronic kidney disease as estimated glomerular filtration rate <60 ml/min/1.73m2. Linear and logistic regression analyses were used to examine the relationship between hyperuricemia and development of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, and overweight/obesity (unadjusted and adjusted for age, sex, smoking, drinking habits, baseline estimated glomerular filtration rate and body mass index). 5,899 subjects without comorbidities (mean age of 47 ± 10 years, 1,864 men) were followed for 5 years. Hyperuricemia (defined as >7 mg/dL in men and ≥6 mg/dL in women) was associated with increased cumulative incidence rates of hypertension (14.9% vs 6.1%, p<0.001), dyslipidemia (23.1% vs 15.5%, p<0.001), chronic kidney disease (19.0% vs 10.7%, p<0.001), and overweight/obesity (8.9% vs 3.0%, p<0.001), while diabetes mellitus (1.7% vs 0.9%, p=0.087) showed a trend but did not reach statistical significance. In conclusion, asymptomatic hyperuricemia carries a significant risk for developing cardiometabolic conditions in Japanese individual without comorbidities.