CD73 mitigates hepatic damage in alcoholic steatohepatitis by regulating PI3K/AKT-mediated hepatocyte pyroptosis.
CD73 mitigates hepatic damage in alcoholic steatohepatitis by regulating PI3K/AKT-mediated hepatocyte pyroptosis.
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DOI：
10.1016/j.bcp.2023.115753
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发表时间：
2023-08
影响因子：
5.8
通讯作者：
Hong Zhu;Mengda Zhang;Ying Ye;Zhenni Liu;Jianpeng Wang;Xue Wu;Xiong-wen Lv
中科院分区：
文献类型：
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作者：
Hong Zhu;Mengda Zhang;Ying Ye;Zhenni Liu;Jianpeng Wang;Xue Wu;Xiong-wen Lv
背景饮酒是死亡和残疾的一个主要危险因素，导致全球重大疾病负担。酒精性脂肪性肝炎（ASH）反映了酒精性肝病（ALD）的急性加重，是全球日益增长的医疗保健和经济负担。焦亡在ASH的发病机制中起核心作用。Nt 5e（CD 73）是一种细胞表面胞外-5 β-核苷酸酶，是将促炎信号ATP转化为抗炎介质腺苷（ADO）的关键酶。研究发现，CD 73与多种疾病有关，并可以缓解gasdermin D（GSDMD）介导的细胞热下垂;目的通过体内外实验研究CD 73介导的肝细胞凋亡在酒精性肝损伤中的作用和机制。方法CD 73基因敲除（CD 73-/-）小鼠、野生型（WT）小鼠、以AML-12细胞为实验对象，观察CD 73对肝细胞凋亡的影响。采用分子生物学和组织学相结合的方法，对肝细胞凋亡进行了研究，并探讨了肝细胞凋亡在体内和体外的机制。在体内，CD 73敲除显著加重肝脏中的炎性损伤、脂质积聚和肝细胞焦亡。在体外，pEGFP-C1/CD 73过表达CD 73可以减少NLRP 3炎性小体的激活和肝细胞的焦亡。进一步分析表明，磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（AKT）信号通路是CD 73调节的可能机制。同时，这一病理过程被抑制后使用PI 3 K inhibitors.ConclusionOur结果表明一种新的功能的CD 73调节肝细胞pyroptosis和突出的治疗机会，减少ALD的疾病过程。
BackgroundAlcohol use is a major risk factor for death and disability, resulting in a significant global disease burden. Alcoholic steatohepatitis (ASH) reflects an acute exacerbation of alcoholic liver disease (ALD) and is a growing health care and economic burden worldwide. Pyroptosis plays a central role in the pathogenesis of ASH. Nt5e (CD73) is a cell surface ecto-5ʹ-nucleotidase, which is a key enzyme that converts the proinflammatory signal ATP to the anti-inflammatory mediator adenosine (ADO). Studies have found that CD73 is involved in multiple diseases and can alleviate gasdermin D (GSDMD)-mediated pyroptosis; however, its role and mechanism in ASH are not explicit.AimTo investigate the role and mechanisms of CD73-mediated hepatocyte pyroptosis in alcohol-induced liver injury through in vivo and in vitro experiments.MethodsCD73 knockout (CD73-/-) mice, wild-type (WT) mice, and AML-12 cells were used to evaluate the effect of CD73 on hepatocyte pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and investigate the mechanism both in vivo and in vitro.ResultsThe protein expression of CD73 and pyroptosis pathway-associated genes was increased significantly in hepatocyte injury model both in vivo and in vitro. In vivo, CD73 knockout dramatically aggravated inflammatory damage, lipid accumulation, and hepatocyte pyroptosis in the liver. In vitro, overexpression of CD73 by pEGFP-C1/CD73 can decrease NLRP3 inflammasome activation and pyroptosis in hepatocytes. Further analysis revealed that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a possible mechanism of CD73 regulation. Meanwhile, this pathological process was inhibited after the use of PI3K inhibitors.ConclusionOur results show a novel function of CD73 regulates hepatocytes pyroptosis and highlights the therapeutic opportunity for reducing the disease process in ALD.