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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.

Background: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-l-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. Methods: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. Results: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. Conclusions: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism. Graphical abstract: