First Department of Internal Medicine, University of Toyama, Toyama, Japan.
Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi, Japan.
J Diabetes Investig. 2019 Nov;10(6):1411-1418. doi: 10.1111/jdi.13047. Epub 2019 Apr 11.
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.
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.
目的/引言：肝脏慢性炎症常与肥胖或 2 型糖尿病同时发生。在这些病理条件下，免疫细胞（如巨噬细胞）在肝癌的发生或发展中起着重要作用。最近有报道称，缺氧诱导因子-1α（HIF-1α）是巨噬细胞获得炎症 M1 极性的关键分子。在本研究中，我们使用巨噬细胞特异性 HIF-1α 敲除（KO）小鼠，研究了巨噬细胞极性改变对肥胖和糖尿病相关肝癌的影响。
为了在小鼠中诱导肝癌，使用化学致癌剂二乙基亚硝胺。KO 小鼠和野生型同窝仔鼠分别喂食高脂肪饮食（HFD）或普通饲料。主要在 HFD 喂养 6 个月后对它们进行分析。
与野生型同窝仔鼠相比，HFD 喂养的 KO 小鼠肝癌的发展减少了 45%。KO 小鼠肝脏中细胞外信号调节激酶 2 的磷酸化也较低。在正常饲料喂养的小鼠中未观察到巨噬细胞中 HIF-1α 缺失的这些作用。此外，即使在 HFD 喂养的情况下，KO 和野生型同窝仔鼠的肝肿瘤大小也没有差异。这些结果表明，HFD 激活巨噬细胞 HIF-1α不是参与肝癌的生长，而是参与增强的癌基因细胞外信号调节激酶 2 信号在肝细胞中的肝癌发生。
巨噬细胞 HIF-1α 的激活可能在与饮食诱导的肥胖和糖尿病相关的肝癌发生中发挥重要作用。
