Background and aims: The molecular mechanisms underlying the promotion of colorectal carcinogenesis by a high-fat diet (HFD) remain unclear. We investigated the role of the insulin-signal pathway and the c-Jun N-terminal kinase (JNK) pathway, which reportedly play crucial roles in insulin resistance, during colorectal carcinogenesis in the presence of hyperinsulinaemia induced by a HFD.
Methods: Azoxymethane-induced aberrant crypt foci formation and cell proliferation in the colonic epithelium were compared between mice fed a normal diet (ND) and mice fed a HFD. A western blot analysis was performed to elucidate the mechanism affecting colorectal carcinogenesis by a HFD.
Results: The number of aberrant crypt foci and the colonic epithelial cell proliferative activity were significantly higher in the HFD group than in the ND group. While the plasma insulin level was significantly higher in the HFD group than in the ND group, a western blot analysis revealed the inactivation of Akt, which is located downstream of the insulin receptor, in the colonic epithelia of the HFD group. On the other hand, JNK activity was significantly higher in the HFD group than in the ND group. A JNK specific inhibitor significantly suppressed the increase in epithelial cell proliferation only under a HFD, but not under a ND.
Conclusions: Colonic cell proliferation was promoted via the JNK pathway in the presence of a HFD but not in the presence of a ND. This novel mechanism may explain the involvement of the JNK pathway in the effect of dietary fat intake on colon carcinogenesis.
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Funding This work was supported in part by a Grant-in-Aid for research on the Third Term Comprehensive Control Research for Cancer from the Ministry on Health, Labor and Welfare, Japan, to AN; a grant from the National Institute of Biomedical Innovation (NBIO) to AN; a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (KIBAN-B), to AN; and a grant program “Collaborative Devlopment of Innovative Seeds” from the Japan Science and Technology Agency (JST).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
See Commentary, p 1575
Ethics approval All animal experiments were approved by the Institutional Animal Care and Use Committee of Yokohama City University School of Medicine.
▸ Supplementary material (a method and four figures) is published online only at http://gut.bmj.com/content/vol58/issue12
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