title: Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10.
abstract: 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/TNFα (M1) and CD163/CD206 (M2) expression using flow cytometry. Role of hif-1α-induced IL-10 was dissected in hepatocyte specific hif-1αKO and hif-1αdPA (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-1α, and livers from hif-1α over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acidin vitroshowed activation of hif-1α and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1α in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1α mediated IL-10 polarizing M2 macrophages.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Ambade
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Satishchandran
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Banishree
authors.initials: B
authors.lastname: Saha
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Benedek
authors.initials: B
authors.lastname: Gyongyosi
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lowe
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.affiliation: Department of Medicine, University of Massachusetts Medical School , Worcester, MA, USA.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
keywords: CD163; DEN; M2c macrophages; epithelial-mesenchymal transition; palmitic acid