Macrophage-specific hypoxia-inducible factor-1a deletion suppresses the development of liver tumors in high-fat diet-fed obese and diabetic mice Akiko Takikawa 1 , Isao Usui 1,2, * , Shiho Fujisaka 1 , Koichi Tsuneyama 3 , Keisuke Okabe 1,4 , Takashi Nakagawa 4 , Allah Nawaz 1 , Tomonobu Kado 1 , Teruo Jojima 2 , Yoshimasa Aso 2 , Yoshihiro Hayakawa 5 , Kunikimi Yagi 1 , Kazuyuki Tobe 1 1 First Department of Internal Medicine, University of Toyama, Toyama, 2 Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi, 3 Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 4 Department of Metabolism and Nutrition, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, and 5 Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan Keywords Hypoxia-inducible factor-1a, Liver cancer, Macrophage *Correspondence Isao Usui Tel.: +81-282-87-2150 Fax: +81-282-86-4632 E-mail address: isaousui-tym@umin.ac.jp J Diabetes Investig, 2019; 10: 1411–1418 doi: 10.1111/jdi.13047 ABSTRACT Aims/Introduction: Chronic inflammation of the liver is often observed with obesity or type 2 diabetes. In these pathological conditions, the immunological cells, such as macrophages, play important roles in the development or growth of liver cancer. Recently, it was reported that hypoxia-inducible factor-1a (HIF-1a) is a key molecule for the acquisi- tion of inflammatory M1 polarity of macrophages. In the present study, we examined the effects of altered macrophage polarity on obesity- and diabetes-associated liver cancer using macrophage-specific HIF-1a knockout (KO) mice. Materials and Methods: To induce liver cancer in the mice, diethylnitrosamine, a chem- ical carcinogen, was used. Both KO mice and wild-type littermates were fed either a high-fat diet (HFD) or normal chow. They were mainly analyzed 6 months after HFD feeding. Results: Development of liver cancer after HFD feeding was 45% less in KO mice than in wild-type littermates mice. Phosphorylation of extracellular signal-regulated kinase 2 was also lower in the liver of KO mice. Those effects of HIF-1a deletion in macrophages were not observed in normal chow-fed mice. Furthermore, the size of liver tumors did not differ between KO and wild-type littermates mice, even those on a HFD. These results suggest that the activation of macrophage HIF-1a by HFD is involved not in the growth, but in the development of liver cancer with the enhanced oncogenic extracellular signal-regu- lated kinase 2 signaling in hepatocytes. Conclusions: The activation of macrophage HIF-1a might play important roles in the development of liver cancer associated with diet-induced obesity and diabetes. INTRODUCTION Liver cancer is one of the representative cancers whose inci- dence increases in patients suffering from metabolic diseases, such as obesity and type 2 diabetes 1–3 . The development of liver cancer is considered to be related to chronic inflammation. For example, it develops more frequently in patients with chronic hepatitis or liver cirrhosis induced by hepatitis virus infection 4,5 . Recently, Karin’s group showed that the activation of tumor necrosis factor or interleukin (IL)-6 signaling is involved in the development of obesity- and diabetes-associated liver cancers using mouse models totally lacking these cytoki- nes 6 . In addition, Ohtani et al. reported that enhanced IL-6 signaling in stellate cells also plays an important role for obe- sity- and diabetes-induced liver cancer. Alteration of intestinal bacteria flora by diet-induced obesity and diabetes increases the production of deoxycholate, which is involved in enhanced IL-6 signaling in stellate cells 7 . These results suggest that obesity- and diabetes-associated alterations in the environmen- tal factors possibly affect the functions not only in hepatocytes, Received 6 September 2018; revised 12 March 2019; accepted 15 March 2019 ª 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 10 No. 6 November 2019 1411 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. ORIGINAL ARTICLE