Obesity phenotype induced by high-fat diet promotes diethylnitrosamine (DEN)-induced precancerous lesions by M1 macrophage polarization in mice liver

Liver precancerous lesions are the key to improving the efficacy of cancer treatment because of the extremely poor prognosis of HCC patients in moderate and late stages. Obesity-related HCC progression is closely related to the inflammatory microenvironment, in which macrophages are one of the major constituents. In the present study, we ask whether obesity promotes diethylnitrosamine (DEN)-induced precancerous lesions by M1 macrophage polarization. First, an association between obesity and liver precancerous lesions was determined by histopathological observations, immunochemistry and immunoblotting. The characteristics of early precancerous lesions (trabecular thickening) appeared earlier eight weeks in obese mice than in normal diet mice after DEN induction. The glutathione S-transferase placental-1 (Gstp 1) and alpha-fetoprotein (AFP) expression in obese mice after DEN induction was higher than that in the same period after DEN injection in normal diet mice. Furthermore, there was a significant increase in the total macrophage number (F4/80(+)) of DEN and M1 macrophage number (CD86(+)F4/80(+)) in obese mice compared with that in normal diet mice. Besides, the expressions of four pro-inflammatory factors in DEN-induced obese mice were significantly higher compared with that in normal diet mice. Additionally, angiogenesis was revealed by immunostaining assay to be associated with the inflammatory response. All the results demonstrate that obesity promotes DEN-induced precancerous lesions by inducing M1 macrophage polarization and angiogenesis.