Resolvin D1 attenuates CCl4 Induced Liver Fibrosis by Inhibiting Autophagy-Mediated HSC activation via AKT/mTOR Pathway.
Resolvin D1 attenuates CCl4 Induced Liver Fibrosis by Inhibiting Autophagy-Mediated HSC activation via AKT/mTOR Pathway.
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Resolvin D1 通过 AKT/mTOR 途径抑制自噬介导的 HSC 激活，从而减轻 CCl4 诱导的肝纤维化
DOI：
10.3389/fphar.2021.792414
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发表时间：
2021
影响因子：
5.6
通讯作者：
Xu K
中科院分区：
文献类型：
--
作者：
Li J;Deng X;Wang S;Jiang Q;Xu K
此前有报道称，RvD1可减轻多种肝病的炎症和肝损伤，但其在肝纤维化中的潜在作用仍不清楚。本研究的目的是探讨RvD1在肝纤维化自噬过程中的作用及其机制。在体内，雄性C57BL/6小鼠每周2次腹腔注射20%四氯化碳(CCl4，5 mg/kg)，共6周，建立肝纤维化模型。在造模期的最后2周，每天加入Rvd1(100 ng或300 ng/只)。在体外，将脂多糖(LPS)激活的LX-2细胞与增加浓度(2.5-10 NM)的RvD1共同处理。通过检测血清AST、ALT含量及H&E染色判断肝损伤程度。用Masson‘s三色染色和METAVIR评分评价肝纤维化程度。采用定量逆转录聚合酶链式反应(QRT-PCR)、免疫印迹、免疫组织化学和免疫荧光等方法对肝组织和脂多糖激活的LX-2细胞进行检测，探讨RvD1对肝纤维化的保护作用。我们的研究结果表明，Rvd1通过降低血浆天冬氨酸转氨酶和丙氨酸氨基转移酶水平，减少I型胶原和α-SMA在小鼠肝脏中的积聚以及其他促纤维化基因(CTFTIMP-1和Vimentin)的表达，恢复受损的组织结构，改善肝纤维化评分，从而显著减轻CCl_4诱导的肝损伤和纤维化。在体外，RvD1还抑制了脂多糖诱导的LX-2细胞的激活和增殖。这些显著的改善主要归因于RvD1对肝星状细胞(HSC)激活过程中自噬的抑制作用，表现为Lc3-II/I比值的降低和P62的升高。此外，利用AZD5363(激活自噬的AKT抑制剂)和AZD8055(mTOR抑制剂，另一种自噬激活剂)，我们进一步证实RvD1抑制自噬介导的HSC激活，并部分通过AKT/mTOR途径减轻CCl4诱导的肝纤维化。总体而言，这些结果表明RvD1治疗有望成为抗肝纤维化的一种新的治疗策略。
Resolvin D1 (RvD1) was previously reported to relieve inflammation and liver damage in several liver diseases, but its potential role in liver fibrosis remains elusive. The aim of our study was to investigate the effects and underlying mechanisms of RvD1 in hepatic autophagy in liver fibrosis. In vivo, male C57BL/6 mice were intraperitoneally injected with 20% carbon tetrachloride (CCl4, 5 ml/kg) twice weekly for 6 weeks to establish liver fibrosis model. RvD1 (100 ng or 300 ng/mouse) was added daily in the last 2 weeks of the modeling period. In vitro, lipopolysaccharide (LPS)-activated LX-2 cells were co-treated with increasing concentrations (2.5–10 nM) of RvD1. The degree of liver injury was measured by detecting serum AST and ALT contents and H&E staining. Hepatic fibrosis was assessed by masson's trichrome staining and metavir scoring. The qRT-PCR, western blot, immunohistochemistry, and immunofluorescence were applied to liver tissues or LPS-activated LX-2 cells to explore the protective effects of RvD1 in liver fibrosis. Our findings reported that RvD1 significantly attenuated CCl4 induced liver injury and fibrosis by decreasing plasma AST and ALT levels, reducing collagen I and α-SMA accumulation and other pro-fibrotic genes (CTGF, TIMP-1 and Vimentin) expressions in mouse liver, restoring damaged histological architecture and improving hepatic fibrosis scores. In vitro, RvD1 also repressed the LPS induced LX-2 cells activation and proliferation. These significant improvements mainly attributed to the inhibiting effect of RvD1 on autophagy in the process of hepatic stellate cell (HSC) activation, as demonstrated by decreased ratio of LC3-II/I and elevated p62 after RvD1 treatment. In addition, using AZD5363 (an AKT inhibitor that activates autophagy) and AZD8055 (an mTOR inhibitor, another autophagy activator), we further verified that RvD1 suppressed autophagy-mediated HSC activation and alleviated CCl4 induced liver fibrosis partly through AKT/mTOR pathway. Overall, these results demonstrate that RvD1 treatment is expected to become a novel therapeutic strategy against liver fibrosis.
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影响因子：
--
作者：
Lippai M;Lőw P
通讯作者：
Lőw P
影响因子：
7.3
作者：
Isopi, Elisa;Mattoscio, Domenico;Recchiuti, Antonio
通讯作者：
Recchiuti, Antonio
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。
影响因子：
5.6
作者：
Li, Jiahuan;Deng, Xiaoling;Xu, Keshu
通讯作者：
Xu, Keshu
影响因子：
32.4
作者：
Buckley, Christopher D.;Gilroy, Derek W.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
3.8
作者：
Barabutis N;Uddin MA;Catravas JD
通讯作者：
Catravas JD