Histone deacetylase 8 inhibition alleviates cholestatic liver injury and fibrosis
Histone deacetylase 8 inhibition alleviates cholestatic liver injury and fibrosis
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DOI：
10.1016/j.bcp.2020.114312
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发表时间：
2021-01-01
影响因子：
5.8
通讯作者：
Park, Byung-Hyun
中科院分区：
文献类型：
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作者：
Lee, Chang Hun;Choi, Yunjung;Park, Byung-Hyun
胆汁淤积症是一种病理状态，涉及胆汁流动阻塞，导致肝毒性、炎症和纤维化。虽然最近的研究表明组蛋白脱乙酰酶(HDACs)参与了不同器官的纤维化进程，但HDAC8在肝纤维化中的作用至今仍不清楚。本研究报道了一种新合成的选择性HDAC8抑制剂SPA3014，它由一个乙烯基二硫代硫醚组成，并评价了其对胆管结扎(BDL)小鼠淤胆性肝损伤和肝纤维化的治疗作用。我们首先观察到胆汁淤积性肝病小鼠和胆汁淤积性肝病患者的HDAC8蛋白水平升高。根据大体检查、组织病理学结果和生化分析，经SPA3014预处理的BDL小鼠的肝脏损伤和纤维化程度低于车辆处理的小鼠。对LX-2人肝星状细胞的研究表明，SPA3014通过抑制转化生长因子-β介导的MAPK-Smad2/3和JAK2-STAT3通路的激活以及上调PPARγ的表达而发挥保护作用。总体而言，这些结果强烈表明，HDAC8抑制构成了治疗淤胆性肝损伤的一种新的治疗策略。
Cholestasis is a pathological condition involving blockage of bile flow that results in hepatotoxicity, inflammation, and fibrosis. Although recent studies have shown that histone deacetylases (HDACs) are involved in the progression of fibrosis in various organs, the role of HDAC8 on liver fibrosis has until now remained unexplored. This study presents a newly-synthesized, selective HDAC8 inhibitor SPA3014 composed of a vinyl disulfidesulfoxide core, and evaluates its therapeutic efficacy against cholestatic liver injury and fibrosis in bile ductligated (BDL) mice. We first observed the increase in HDAC8 protein levels in mice with BDL and patients with cholestatic liver disease. Mice with BDL that were pretreated with SPA3014 had lower liver damage and fibrosis, based on gross examination, histopathologic findings, and biochemical analyses, than did vehicletreated mice. Studies with LX-2 human hepatic stellate cells showed that SPA3014 exerted protective effects by inhibiting TGF-beta-mediated activation of MAPK-Smad2/3 and JAK2-STAT3 pathways and by upregulating PPAR gamma expression. Overall, these results strongly suggest that HDAC8 inhibition constitutes a new therapeutic strategy for treatment of cholestatic liver injury.