Abstract
Recent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose-treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is increasingly common, its prevalence rising in parallel with that of the metabolic syndrome under the influence of a western diet
Recent research has revealed the impact of a western diet, high fructose consumption, on augmentation of inflammation in non-alcoholic steatohepatitis (NASH) related to various factors, such as insulin resistance, hepatic fat accumulation, or increases intestinal permeability [3]
It has not been proven whether fructose intake promotes progression of NASH by inducing liver fibrosis or hepatocarcinogenesis
Summary
Nonalcoholic fatty liver disease (NAFLD) is increasingly common, its prevalence rising in parallel with that of the metabolic syndrome under the influence of a western diet. The multiple parallel hits hypothesis suggests that various factors, including the metabolic syndrome with visceral fat accumulation or insulin resistance, oxidative stress, or endotoxins such as lipopolysaccharide (LPS), act synchronously on the liver to induce NASH [2]. It has been reported that concomitant treatment with antibiotics almost blocked the effect of fructose on the mouse liver [6] as well as on rat metabolic syndrome, inflammation and oxidative stress [12]. Fructose is reported to worsen inflammation in clinical NASH [13, 14] Based on these findings, it is clear that high fructose intake exacerbates hepatic inflammation in NASH by inducing intestinal permeability and increased portal blood LPS concentrations. The mechanism by which fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH has yet to be clarified
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