Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1alphainduced IL-10
Department of Medicine, Division of Gastroenterology; UMass Metabolic Network
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Immunology and Infectious Disease | Molecular Biology
Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFalpha (M1) and CD163/CD206 (M2) expression using flow cytometry. Role of hif-1alpha-induced IL-10 was dissected in hepatocyte specific hif-1alphaKO and hif-1alphadPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN + HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/80+CD11b+) infiltration to liver and DEN + HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1alpha, and livers from hif-1alpha over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1alpha and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1alpha in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1alpha mediated IL-10 polarizing M2 macrophages.
CD163, DEN, M2c macrophages, epithelial-mesenchymal transition, palmitic acid
DOI of Published Version
Oncoimmunology. 2016 Sep 26;5(10):e1221557. eCollection 2016. Link to article on publisher's site
Ambade A, Satishchandran A, Saha B, Gyongyosi B, Lowe P, Kodys K, Catalano D, Szabo G. (2016). Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1alphainduced IL-10. UMass Metabolic Network Publications. https://doi.org/10.1080/2162402X.2016.1221557. Retrieved from https://escholarship.umassmed.edu/metnet_pubs/30