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首页> 外文期刊>Cell death discovery. >Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress
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Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress

机译：通过AMPK / PI3K / AKT介导的氧化应激促进肝脏常规巨噬细胞促炎反应，高血糖会加剧乙酰氨基酚诱导的急性肝损伤

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Although diabetes mellitus/hyperglycemia is a risk factor for acute liver injury, the underlying mechanism remains largely unknown. Liver-resident macrophages (Kupffer cells, KCs) and oxidative stress play critical roles in the pathogenesis of toxin-induced liver injury. Here, we evaluated the role of oxidative stress in regulating KC polarization against acetaminophen (APAP)-mediated acute liver injury in a streptozotocin-induced hyperglycemic murine model. Compared to the controls, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation. KCs obtained from hyperglycemic mice secreted higher levels of the proinflammatory factors, such as TNF-α and IL-6, lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced oxidative stress was revealed by increased levels of reactive oxygen species (ROS) in KCs from hyperglycemic mice post APAP treatment. In addition, ROS inhibitor NAC resulted in a significant decrease of ROS production in hyperglycemic KCs from mice posttreated with APAP. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia promoted M1 polarization, but inhibited M2 polarization of KCs obtained from APAP-exposed livers, as evidenced by increased MCP-1 and inducible NO synthase (iNOS) gene induction but decreased Arg-1 and CD206 gene induction accompanied by increased STAT1 activation and decreased STAT6 activation. NAC restored Arg-1, CD206 gene induction, and STAT6 activation. To explore the mechanism how hyperglycemia regulates KCs polarization against APAP-induced acute liver injury, we examined the AMPK/PI3K/AKT signaling pathway and found decreased AMPK activation and increased AKT activation in liver and KCs from hyperglycemic mice post APAP treatment. AMPK activation by its agonist AICAR or PI3K inhibition by its antagonist LY294002 inhibited ROS production in KCs from hyperglycemic mice post APAP treatment and significantly attenuated APAP-induced liver injury in the hyperglycemic mice, compared to the control mice. Our results demonstrated that hyperglycemia exacerbated APAP-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress.
机译：虽然糖尿病/高血糖是急性肝损伤的危险因素，但下面的机制仍然很大程度上是未知的。肝脏常规巨噬细胞（Kupffer细胞，KCs）和氧化应激在毒素诱导的肝损伤的发病机制中起重要作用。在此，我们评估了氧化应激在用于调节链脲佐菌素诱导的高血糖鼠模型中对乙酰氨基酚（APAP）介导的急性肝损伤的KC偏振的作用。与对照相比，高血糖小鼠表现出肝损伤和肝内炎症的显着增加。从高血糖小鼠获得的KCs分泌更高水平的促炎因子，例如TNF-α和IL-6，抗炎因子IL-10的较低水平。此外，通过高血糖小鼠在APAP治疗后的高血糖小鼠中的活性氧物质（ROS）水平增加，揭示了增强的氧化应激。此外，ROS抑制剂NAc导致来自用APAP的小鼠的小鼠高血糖KC的ROS产生显着降低。我们还分析了高血糖在巨噬细胞M1 / M2极化中的作用。有趣的是，我们发现高血糖促进了M1偏振，但抑制了从APAP暴露肝脏获得的KC的M2偏振，如通过增加的MCP-1和诱导的NO合成酶（INOS）基因诱导所证明，但伴随的ARG-1和CD206基因感应伴随提高STAT1激活并减少STAT6激活。 NAC恢复了ARG-1，CD206基因诱导和Stat6激活。为了探索机制，高血糖如何调节KCS对APAP诱导的急性肝损伤的偏振，我们检查了AMPK / PI3K / AKT信号通路，发现肝脏和KC中的AMPK活化和增加的AKT激活增加了肝脏后APAP治疗。通过其激动剂AICAR或PI3K抑制的AMPK活化通过其拮抗剂LY294002抑制了从高血糖小鼠的KCS中的ROS产生，并且与对照小鼠相比，高血糖治疗后的高血糖小鼠和高血糖小鼠的APAP诱导的肝损伤。我们的结果表明，通过AMPK / PI3K / AKT介导的氧化应激促进肝脏常规巨噬细胞促炎反应，高血糖诱导的APAP诱导的急性肝损伤。

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