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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‐1α (HIF ‐1α) is a key molecule for the acquisition 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 ‐1α knockout (KO) mice.    Materials and Methods  To induce liver cancer in the mice, diethylnitrosamine, a chemical 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 ‐1α 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 ‐1α by  HFD  is involved not in the growth, but in the development of liver cancer with the enhanced oncogenic extracellular signal‐regulated kinase 2 signaling in hepatocytes.    Conclusions  The activation of macrophage  HIF ‐1α might play important roles in the development of liver cancer associated with diet‐induced obesity and diabetes.

Macrophage‐specific hypoxia‐inducible factor‐1α deletion suppresses the development of liver tumors in high‐fat diet‐fed obese and diabetic mice