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

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.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.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.The activation of macrophage HIF-1α might play important roles in the development of liver cancer associated with diet-induced obesity and diabetes.