De novo lipogenesis is required for insulin-mediated hepatocarcinogenesis and contributes to human liver cancer prognosis

To study the oncogenic effect of chronic and elevated secretion of insulin on hepatocytes in the presence of mild hyperglycemia, we developed a model of pancreatic islet transplantation into the liver via the portal vein. In this model, islets of a donor rat are transplanted into the liver of a recipient diabetic rat, with resulting local hyperinsulinism that leads to the development of preneoplastic lesions and hepatocellular carcinoma (HCC). Here, we analyzed the activation of the lipogenic pathway in rat preneoplastic lesions and HCC. The results were compared with those obtained in a collection of human HCC and corresponding non-tumorous surrounding tissues. The role on HCC growth of FASN, ACAC, ACLY, and SCD lipogenic proteins was evaluated via transfection and siRNA approaches in human HCC cell lines. We found a strong induction of the proteins of the lipogenic pathway (ACLY, ACAC, FASN, SCD, HMGCR, CHREBP, LXR, SREBP1 and 2) in rat and human liver lesions. In the latter, induction of the lipogenic pathway was inversely correlated with patients’ survival and activation of the AMPK pathway, and directly correlated with activation of the insulin/IGF-1R cascade. In human HCC cell lines, siRNA and transfection experiments showed that the PI3K/AKT/mTOR pathway was responsible for activation of the lipogenic cascade. Insulin administration significantly increased HCC cell growth in vitro, which was strongly restrained by inhibition of the lipogenic proteins. In particular, suppression of ACLY, ACAC, FASN, and SCD lipogenic proteins by specific siRNAs and soluble inhibitors was highly detrimental for the proliferation and survival of HCC cell lines. Our results assign a pathogenetic and prognostic significance to insulin-driven hepatocarcinogenesis and the lipogenic cascade in rodent and human HCC. Furthermore, the present findings open the possibility of inhibiting the lipogenic cascade as a novel therapeutic approach for the treatment of human HCC.

ACAC - ACLY - AKT - ATP-Citrat-Lyase - Acetyl-CoA-Carboxylase - CHREBP - FASN - Fatty Acid Synthase - HCC - HMGCR - Hepatocarcinogenesis - Insulin - SCD - SRBEP2 - SREBP1 - Stearoyl-CoA-Desaturase - mTOR