Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA, 30322, USA.
Transplant Services, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Apoptosis. 2021 Jun;26(5-6):361-370. doi: 10.1007/s10495-021-01673-1. Epub 2021 May 14.
A steatotic liver is increasingly vulnerable to ischemia reperfusion injury (IRI), and the underlying mechanisms are incompletely defined. Caspases are endo-proteases, which provide critical regulatory connections between cell death and inflammation. Caspase 1 is driven by inflammasomes which are key signaling platforms, that detect sterile stressors (DAMPs), releasing the highly pro-inflammatory cytokine interleukin IL-8 and IL-1β. To delineate the involvement of Caspase 1 and 11 in hepatocellular injury in steatotic liver undergoing IRI. Male C57BL6/Wild Type and Caspase 1, Caspase 11 and Caspase 1/11 mice were fed a high fat diet (HFD) for 12 weeks. These mice were subjected to 40 min of ischemia followed by 2-24 h of reperfusion. Hepatocellular injury was assessed by histopathologic injury scoring, serum ALT and propidium iodide (PI) uptake, mRNA levels of Caspase 1, IL-1β by RT PCR, Caspase 1 activity assay and Caspase 1. Specific Caspase 1, inhibitor experiments were carried out. All groups gained similar body weight after a 12-week HFD. Cleaved Caspase 1 protein levels, Caspase 1 mRNA levels were significantly higher in steatotic liver undergoing IRI. Executor of pyroptosis cleaved GSDMD levels were higher in HFD fed mouse compared to lean. In addition, genetic deletion of Caspase 1, Casp1 mouse expressing Caspase-11 and Caspase 1/11 double knock out demonstrated significant reduction in serum ALT (p < 0.01), Injury Score, (p < 0.0002) but not in Caspase 11 alone. Caspase 1 is the driver of hepatocellular injury in a steatotic liver undergoing IRI, inhibition of which leads to hepatoprotection, thus providing a therapeutic target for clinical use.
脂肪肝越来越容易受到缺血再灌注损伤（IRI）的影响，但其潜在机制尚不完全明确。半胱天冬酶是内肽酶，为细胞死亡和炎症之间提供了关键的调节连接。半胱天冬酶 1 由炎症小体驱动，炎症小体是检测无菌应激源（DAMPs）的关键信号平台，可释放高度促炎细胞因子白细胞介素 IL-8 和 IL-1β。为了阐明 Caspase 1 和 11 在经历 IRI 的脂肪肝肝细胞损伤中的作用。雄性 C57BL6/WT 和 Caspase 1、Caspase 11 和 Caspase 1/11 小鼠喂食高脂肪饮食（HFD）12 周。这些小鼠接受 40 分钟的缺血，然后再灌注 2-24 小时。通过组织病理学损伤评分、血清 ALT 和碘化丙啶（PI）摄取、RT-PCR 测定 Caspase 1 和 IL-1βmRNA 水平、Caspase 1 活性测定和 Caspase 1 测定评估肝细胞损伤。进行了 Caspase 1 特异性抑制剂实验。所有组在 12 周 HFD 后体重增加相似。经历 IRI 的脂肪肝中 Caspase 1 蛋白水平和 Caspase 1 mRNA 水平显著升高。与瘦鼠相比，高脂饮食喂养的小鼠中促炎细胞程序性细胞死亡的执行者 GSDMD 水平升高。此外，Caspase 1 基因缺失、表达 Caspase-11 的 Casp1 小鼠和 Caspase 1/11 双敲除小鼠的血清 ALT（p < 0.01）、损伤评分（p < 0.0002）显著降低，但 Caspase 11 单独缺失则没有。Caspase 1 是经历 IRI 的脂肪肝肝细胞损伤的驱动因素，抑制其表达可导致肝保护，因此为临床应用提供了一个治疗靶点。
