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.Keywords: Acute inflammation; Kupffer cells.

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乐备实（上海优宁维生物科技股份有限公司旗下全资子公司），是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
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