Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int Immunopharmacol. 2020 Nov;88:106961. doi: 10.1016/j.intimp.2020.106961. Epub 2020 Oct 13.
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.
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.
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-κB and MAPK signalling pathways as well as enhancing antioxidation capacity via the activation of the Nrf2 pathway.
These results demonstrate that RvD1 is a promising hepatoprotective agent for the therapy of NASH.
解析素 D1（RvD1）是一种从二十二碳六烯酸（DHA）转化而来的强效内源性脂质介质，在许多临床前疾病模型中具有抗炎和抗氧化作用，但它在非酒精性脂肪性肝炎（NASH）中的潜在作用仍不清楚。本研究旨在探讨 RvD1 在 NASH 中的保护作用及其机制。
体内实验中，雄性 C57BL/6 小鼠用 MCD 饮食喂养 4 周以诱导 NASH，在喂养的最后 2 周添加 RvD1。体外实验中，用不同浓度的 RvD1预处理脂多糖（LPS）激活的 RAW264.7 巨噬细胞。通过生化方法测定血清肝功能标志物和肝氧化应激指标。用苏木精-伊红、油红 O 和 Masson 三色染色法染色小鼠肝组织切片，以评估肝炎、脂肪变性和纤维化的严重程度。应用 qRT-PCR、免疫组织化学和 Western blot 检测分析 RvD1 对 NASH 保护作用的机制。
体内，RvD1 通过调节关键事件，如 NASH 进展过程中的脂肪变性、炎症、氧化应激和纤维化，显著减轻 MCD 饮食喂养小鼠的肝炎。体外，RvD1 还抑制 LPS 诱导的 RAW264.7 细胞炎症。这些作用可能主要归因于 RvD1 通过抑制 TLR4-MyD88 介导的 NF-κB 和 MAPK 信号通路，显著抑制过度的炎症反应，以及通过激活 Nrf2 通路增强抗氧化能力。
这些结果表明 RvD1 是治疗 NASH 的一种有前途的肝保护剂。
