Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers. Surprisingly, livers from ZnR/GPR39 knockout (KO) mice exhibited elevated insulin receptor expression and downstream AKT activation. Moreover, ZnR/GPR39 KO mice had higher blood fasting glucose level, pronounced hepatic lipid accumulation, increased hepatocyte oxygen consumption rate (OCR) and reactive oxygen species (ROS) levels. These data suggest that ZnR/GPR39 modulates insulin receptor signaling, a major pathway in hepatic metabolism. Associated with the impaired signaling, ZnR/GPR39 KO livers exhibited increased tissue fibrosis, manifested by marked elevation of collagen expression, compared to wildtype (WT). Additionally, we found alteration of hepatocyte junctional proteins that was accompanied by increased macrophage infiltration and higher liver inflammation in ZnR/GPR39 KO mice. To determine the role of ZnR/GPR39 in ALI, we applied a mild LPS challenge that induced profound decrease in hepatic OCR, also leading to higher ROS generation in ZnR/GPR39 KO hepatocytes, but not in WT. We further found increased serum IL-2 and AST/ALT ratio only in ZnR/GPR39 KO mice. Our findings reveal a role of ZnR/GPR39 in controlling hepatic insulin receptor signaling and mitigating liver fibrosis and inflammation, thus underscoring the important role of ZnR/GPR39 in liver signaling and function.

中文翻译：

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ZnR/GPR39 调节肝脏胰岛素信号传导，调节肝脏生物能量学和 ROS 产生，并减轻肝纤维化和损伤


锌的充足供应对肝功能至关重要，锌的缺乏与急性肝损伤 （ALI） 和慢性非酒精性脂肪性肝病 （NAFLD） 有关。然而，锌如何控制肝功能尚不清楚。我们发现锌敏感的 ZnR/GPR39 是锌信号传导的介质，可增强肝脏对 ERK1/2 的磷酸化，而 ERK1/2 在 ZnR/GPR39 缺陷的肝脏中磷酸化会降低。令人惊讶的是，来自 ZnR/GPR39 敲除 （KO） 小鼠的肝脏表现出胰岛素受体表达升高和下游 AKT 激活。此外，ZnR/GPR39 KO 小鼠具有较高的空腹血糖水平、明显的肝脂质积累、肝细胞耗氧率 （OCR） 和活性氧 （ROS） 水平增加。这些数据表明 ZnR/GPR39 调节胰岛素受体信号传导，胰岛素受体信号传导是肝脏代谢的主要途径。与野生型 （WT） 相比，ZnR/GPR39 KO 肝脏与信号传导受损相关，表现为胶原蛋白表达显着升高。此外，我们发现肝细胞连接蛋白的改变伴随着 ZnR/GPR39 KO 小鼠巨噬细胞浸润的增加和肝脏炎症的增加。为了确定 ZnR/GPR39 在 ALI 中的作用，我们应用了温和的 LPS 攻击，诱导肝脏 OCR 显着降低，也导致 ZnR/GPR39 KO 肝细胞中 ROS 的产生更高，但在 WT 中则没有。我们进一步发现仅在 ZnR/GPR39 KO 小鼠中血清 IL-2 和 AST/ALT 比率增加。我们的研究结果揭示了 ZnR/GPR39 在控制肝胰岛素受体信号传导和减轻肝纤维化和炎症中的作用，从而强调了 ZnR/GPR39 在肝脏信号传导和功能中的重要作用。