Resolvin D1 mitigates non-alcoholic steatohepatitis by suppressing the TLR4-MyD88-mediated NF-κB and MAPK pathways and activating the Nrf2 pathway in mice
Resolvin D1 mitigates non-alcoholic steatohepatitis by suppressing the TLR4-MyD88-mediated NF-κB and MAPK pathways and activating the Nrf2 pathway in mice
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Resolvin D1 通过抑制 TLR4-MyD88 介导的 NF-κB 和 MAPK 通路并激活小鼠中的 Nrf2 通路来减轻非酒精性脂肪性肝炎。
DOI：
10.1016/j.intimp.2020.106961
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发表时间：
2020-11-01
影响因子：
5.6
通讯作者：
Xu, Keshu
中科院分区：
文献类型：
--
作者：
Li, Jiahuan;Deng, Xiaoling;Xu, Keshu
目的：Resolvin D1（RvD 1）是一种由二十二碳六烯酸（DHA）转化而来的内源性脂质介质，在许多临床前疾病模型中发挥抗炎和抗氧化作用，但其在非酒精性脂肪性肝炎（NASH）中的潜在作用尚不清楚。本研究旨在探讨RvD 1对NASH的保护作用及其机制。主要方法：在体内，雄性C57 BL/6小鼠饲喂MCD饲料4周，诱导NASH。在饲喂期的最后2周添加RvD 1。在体外，脂多糖（LPS）激活的RAW264.7巨噬细胞预处理浓度增加的RvD 1。生化检测血清肝功能指标和肝脏氧化应激指标。小鼠肝组织切片用苏木精-伊红、油红O和Masson三色染色以评估脂肪性肝炎、脂肪变性和纤维化的严重程度。采用qRT-PCR、免疫组织化学和Western印迹分析RvD 1在NASH.Key发现中的保护机制：在体内，RvD 1通过调节关键事件，包括NASH进展中的脂肪变性、炎症、氧化应激和纤维化，显著减轻MCD饮食喂养小鼠的脂肪性肝炎。在体外，RvD 1还抑制RAW 264.7细胞中LPS诱导的炎症。这些作用可能主要归因于RvD 1通过抑制TLR 4-MyD 88介导的NF-κ B和MAPK信号通路显著抑制过度炎症反应，以及通过激活Nrf 2通路增强抗氧化能力。
Aims: Resolvin D1 (RvD1), a potent endogenous lipid mediator converted from docosahexaenoic acid (DHA), has exert anti-inflammatory and antioxidant effects in many preclinical disease models, but its potential role in non-alcoholic steatohepatitis (NASH) remains elusive. This study was performed to investigate the protective effects and mechanisms of RvD1 in NASH.Main methods: In vivo, male C57BL/6 mice were fed an MCD diet for 4 weeks to induce NASH. RvD1 was added in the last 2 weeks of the feeding period. In vitro, lipopolysaccharide (LPS)-activated RAW264.7 macrophages were pretreated with increasing concentrations of RvD1. Serum liver functional markers and hepatic oxidative stress indicators were measured biochemically. Mouse liver tissue sections were stained with hematoxylin-eosin, oil red O, and Masson's trichrome to assess the severity of steatohepatitis, steatosis and fibrosis. The qRT-PCR, immunohistochemistry and Western blotting assays were applied to analyse mechanisms underlying RvD1 protection in NASH.Key findings: In vivo, RvD1 significantly attenuates steatohepatitis in MCD diet-fed mice by modulating key events, including steatosis, inflammation, oxidative stress and fibrosis in the progression of NASH. In vitro, RvD1 also represses LPS-induced inflammation in RAW264.7 cells. These effects may be mainly attributed to RvD1 markedly suppressing excessive inflammatory responses via the inhibition of the TLR4-MyD88-mediated NF-kappa B and MAPK signalling pathways as well as enhancing antioxidation capacity via the activation of the Nrf2 pathway.Significance: These results demonstrate that RvD1 is a promising hepatoprotective agent for the therapy of NASH.