Voltage‐gated proton channels (Hv1/VSOP), encoded by Hvcn1, are important regulator of reactive oxygen species (ROS) production in many types of immune cells. While in vitro studies indicate that Hv1/VSOP regulates ROS production by maintaining pH homeostasis, there are few studies investigating the functional importance of Hv1/VSOP in vivo. In the present study, we first show that Hv1/VSOP is functionally expressed in liver resident macrophage, Kupffer cells, regulating the hepatic oxidative stress in vivo. Our immunocytochemistry and electrophysiology data showed that Hvcn1 is specifically expressed in Kupffer cells, but not in hepatocytes. Furthermore, Hvcn1‐deficiency drastically altered the hepatic oxidative stress. The Hvcn1‐deficient mice showed high blood glucose and serum insulin but normal insulin sensitivity, indicating that these phenotypes were not linked to insulin resistance. Transcriptome analysis indicated that the gene expression of glycogen phosphorylase (Pygl) and Glucose‐6‐phosphatase, catalytic subunit (G6pc) were upregulated in Hvcn1‐deficient liver tissues, and quantitative PCR confirmed the result for Pygl. Furthermore, we observed higher amount of glucose‐6‐phosphate, a key sugar intermediate for glucose in Hvcn1‐deficient liver than WT, suggesting that glucose production in liver is accelerated in Hvcn1‐deficient mice. The present study sheds light on the functional importance of Kupffer cells in hepatic oxidative stress and its potential relationship with glucose metabolism.

中文翻译：

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Kupffer细胞电压门控质子通道（Hv1/VSOP）对肝脏氧化应激的调节及其与葡萄糖代谢的潜在关系

由 Hvcn1 编码的电压门控质子通道 (Hv1/VSOP) 是许多类型免疫细胞中活性氧 (ROS) 产生的重要调节器。虽然体外研究表明 Hv1/VSOP 通过维持 pH 稳态来调节 ROS 的产生，但很少有研究调查 Hv1/VSOP 在体内的功能重要性。在本研究中，我们首先表明 Hv1/VSOP 在肝脏驻留巨噬细胞库普弗细胞中功能表达，在体内调节肝脏氧化应激。我们的免疫细胞化学和电生理学数据显示 Hvcn1 在库普弗细胞中特异性表达，但不在肝细胞中表达。此外，Hvcn1 缺乏显着改变了肝脏氧化应激。Hvcn1 缺陷小鼠表现出高血糖和血清胰岛素，但胰岛素敏感性正常，表明这些表型与胰岛素抵抗无关。转录组分析表明，糖原磷酸化酶 (Pygl) 和葡萄糖 6-磷酸酶催化亚基 (G6pc) 在 Hvcn1 缺陷肝组织中的基因表达上调，定量 PCR 证实了 Pygl 的结果。此外，我们观察到葡萄糖-6-磷酸酯的含量高于 WT，这是 Hvcn1 缺陷型肝脏中葡萄糖的关键糖中间体，这表明 Hvcn1 缺陷型小鼠肝脏中葡萄糖的产生加速。本研究阐明了库普弗细胞在肝脏氧化应激中的功能重要性及其与葡萄糖代谢的潜在关系。催化亚基（G6pc）在 Hvcn1 缺陷肝组织中上调，定量 PCR 证实了 Pygl 的结果。此外，我们观察到葡萄糖-6-磷酸酯的含量高于 WT，这是 Hvcn1 缺陷型肝脏中葡萄糖的关键糖中间体，这表明 Hvcn1 缺陷型小鼠肝脏中葡萄糖的产生加速。本研究阐明了库普弗细胞在肝脏氧化应激中的功能重要性及其与葡萄糖代谢的潜在关系。催化亚基（G6pc）在 Hvcn1 缺陷肝组织中上调，定量 PCR 证实了 Pygl 的结果。此外，我们观察到葡萄糖-6-磷酸酯的含量高于 WT，这是 Hvcn1 缺陷型肝脏中葡萄糖的关键糖中间体，这表明 Hvcn1 缺陷型小鼠肝脏中葡萄糖的产生加速。本研究阐明了库普弗细胞在肝脏氧化应激中的功能重要性及其与葡萄糖代谢的潜在关系。