Oral administration of fructose exacerbates liver fibrosis and hepatocarcinogenesis via increased intestinal permeability in a rat steatohepatitis model
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Kenichiro Seki1, Mitsuteru Kitade1, Norihisa Nishimura1, Kosuke Kaji1, Kiyoshi Asada1, Tadashi Namisaki1, Kei Moriya1, Hideto Kawaratani1, Yasushi Okura1, Hiroaki Takaya1, Yasuhiko Sawada1, Shinya Sato1, Keisuke Nakanishi1 and Hitoshi Yoshiji1
1Third Department of Internal Medicine, Nara Medical University, Nara, Japan
Mitsuteru Kitade, email: firstname.lastname@example.org
Keywords: non-alcoholic steatohepatitis (NASH); fructose; hepatocarcinogenesis; intestinal permeability; endotoxin
Received: December 15, 2017 Accepted: May 24, 2018 Published: June 19, 2018
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.
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