Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation-induced hepatic ischemia-reperfusion injury by regulating the AKT/GSK3 beta/NF-kappa B and AKT/mTOR pathways in rat Kupffer cells
Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation-induced hepatic ischemia-reperfusion injury by regulating the AKT/GSK3 beta/NF-kappa B and AKT/mTOR pathways in rat Kupffer cells
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辛二酰苯胺异羟肟酸通过调节大鼠 Kupffer 细胞中 AKT/GSK3 beta/NF-kappa B 和 AKT/mTOR 通路减轻原位肝移植引起的肝缺血再灌注损伤
DOI：
10.3892/ijmm.2020.4551
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Li Shengwei
中科院分区：
文献类型：
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作者：
Wang Jingyuan;Deng Minghua;Wu Hao;Wang Menghao;Gong Jianping;Bai He;Wu Yakun;Pan Junjiang;Chen Yong;Li Shengwei
肝脏缺血再灌注损伤（IRI）的调控机制多种多样，其中肝脏巨噬细胞库普弗细胞（KCs）通过调节炎症反应和免疫应答发挥重要作用。辛二酰苯胺异羟肟酸（SAHA）是一种泛组蛋白去乙酰化酶抑制剂，具有抗炎作用并诱导自噬。为探讨SAHA是否能改善IRI及其作用机制，建立了大鼠原位肝移植模型。结果表明，SAHA通过抑制AKT/糖原合成酶激酶（GSK）3 β/NF-κ B信号通路，减少KCs的M1极化，从而有效改善OLT诱导的IRI。SAHA通过AKT/mTOR信号通路上调KCs自噬蛋白5（ATG 5）/LC 3B，抑制ATG 5抑制KCs自噬可部分削弱SAHA对IR肝损伤的保护作用。因此，目前的研究表明，SAHA通过抑制AKT/GSK 3 β/NF-κ B通路减少KCs的M1极化，并通过AKT/mTOR信号通路上调KCs中的自噬，这两者都减轻了OLT诱导的IRI。目前的研究表明，SAHA可能是一种新的治疗改善OLT诱导的IRI。
Multiple mechanisms are involved in regulating hepatic ischemia-reperfusion injury (IRI), in which Kupffer cells (KCs), which are liver-resident macrophages, play critical roles by regulating inflammation and the immune response. Suberoylanilide hydroxamic acid (SAHA), a pan-histone deacetylase inhibitor, has anti-inflammatory effects and induces autophagy. To investigate whether SAHA ameliorates IRI and the mechanisms by which SAHA exerts its effects, an orthotopic liver transplantation (OLT) rat model was established after treatment with SAHA. The results showed that SAHA effectively ameliorated OLT-induced IRI by reducing M1 polarization of KCs through inhibition of the AKT/glycogen synthase kinase (GSK)3 beta/NF-kappa B signaling pathway. Furthermore, the present study found that SAHA upregulates autophagy 5 protein (ATG5)/LC3B in KCs through the AKT/mTOR signaling pathway and inhibition of autophagy by knockdown of ATG5 in KCs partly impaired the protective effect of SAHA on IR-injured liver. Therefore, the current study demonstrated that SAHA reduces M1 polarization of KCs by inhibiting the AKT/GSK3 beta/NF-kappa B pathway and upregulates autophagy in KCs through the AKT/mTOR signaling pathway, which both alleviate OLT-induced IRI. The present study revealed that SAHA may be a novel treatment for the amelioration of OLT-induced IRI.