Uric Acid Elevation by Fructose Overload Exacerbates Nash and Atherosclerosis via Oxidative Stress

Background: Nonalcoholic steatohepatitis (NASH) is well associated with an increased risk of cardiovascular disease (CVD), regardless of risk factors for metabolic syndrome. However, intermediary factors between NASH and CVD remain unknown. In recent years, hyperuricemia has been associated not only with gout but also with several other organ diseases, such as hypertension, chronic renal failure, and metabolic syndrome. In addition, hyperuricemia was shown to frequently occur in patients with NASH and could be a risk factor for CVD. Furthermore, serum uric acid (UA) levels have been linked with fructose intake.Objectives: We hypothesized that fructose loading elevates UA levels and exacerbates NASH and atherosclerosis via oxidative stress.Methods: Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr), between 14 to 24 weeks of age, were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet. In addition to the HFC diet, the fructose group was subjected to 10% fructose loading. The oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed at 25-week-old, followed by blood sampling, animal sacrifice, endothelial function test, blood biochemistry, histopathological staining, xanthine oxidase activity test, and genetic analysis performed at 26-week-old.Results: Fructose loading increased UA and oxidative stress levels. In addition, fructose loading induced insulin resistance. The fructose group exhibited aggravated hepatic fibrosis and lipid deposition, as well as enhanced lipid accumulation in the mesenteric arteries.Conclusion: In the SHRSP5/Dmcr rat model, elevated UA levels were a risk factor for the exacerbation of NASH and atherosclerosis via oxidative stress.