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Shen Li*, Sarani Ghoshal, Derek J. Erstad, Gunisha Arora, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs
Surgery, Massachusetts General Hospital, Allston, MA

Hepatocellular carcinoma (HCC) due to non-alcoholic steatohepatitis (NASH) is rising at an alarming rate. Anti-hyperglycemic agents have garnered interests for their potential anti-fibrotic as well as chemo-preventive effects. Pioglitazone, a selective PPAR-γ agonist, has been shown to reduce NASH, but its role as an anti-fibrotic and chemo-preventive agent has yet to be elucidated. The hypothesis of this study is that Pioglitazone reduces inflammation, fibrosis and subsequent HCC development in mice with diethylnitrosamine (DEN) and subsequent diet induced liver injury.

Male C57BL/6J mice received a single intraperitoneal injection of 25mg/kg DEN at day 15 followed by the initiation of a choline-deficient, L amino acid defined, high fat diet (CDAHFD) at 6 weeks of age. DEN+CDAHFD-injured mice were randomized to receive oral gavage of pioglitazone (n=7) or vehicle control (n=9) at 12 weeks of age and were sacrificed at 30 weeks of age after development of HCC in the setting of non-alcoholic steatohepatitis (NASH).

Treatment with pioglitazone resulted in a 56% reduction of surface nodules relative to treatment with vehicle (5.9±1.8 vs. 13.2±1.2; p<0.01). The ratio of liver to body weight was lowered with pioglitazone (p<0.001). Liver sections were stained by picrosirius red to assess fibrosis. Pioglitazone significantly reduced collagen deposition in DEN+CDAHFD-injured mice (collagen proportional area=7.3±1.5 vs. 12.0±1; p<0.05). This histologic observation was further confirmed by gene expression analysis with reduction in several pro-fibrotic markers, such as alpha-smooth muscle actin, collagen type I, transforming growth factor beta, and TIMP1. Pioglitazone also reduced the expressions of inflammatory cytokines such as interleukin 6, interferon gamma and CD68. Pioglitazone treatment resulted in an upregulation of Adiponectin, which has been shown to antagonize oncogenesis. Further evaluation demonstrated that Pioglitazone treatment resulted in an upregulation of AMPK, a well-recognized target for anti-tumor drug discovery while supressing the mitogen-activated protein kinase (MAPK) pathway.

Conclusion: Overall our data supports the hypothesis that the anti-diabetic agent pioglitazone may be repurposed as a drug to reduce fibrosis and prevent HCC. This could be beneficiary in patient management given the low cost as well as minimal side effects.

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