Lipotoxic Hepatocyte-Derived Exosomal MicroRNA 192-5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease.
Lipotoxic Hepatocyte-Derived Exosomal MicroRNA 192-5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease.
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非酒精性脂肪肝中脂毒性肝细胞源性外泌体 miR-192-5p 通过 Rictor/Akt/Forkhead Box 转录因子 O1 信号激活巨噬细胞
DOI：
10.1002/hep.31050
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肝巨噬细胞可被多种因素激活，如源自肠道的细菌成分以及受损肝细胞释放的因子。巨噬细胞向促炎表型（M1）极化是非酒精性脂肪性肝病（NAFLD）疾病进展中的一个重要事件。然而，其潜在的分子机制仍未完全明晰。外泌体已被确认为细胞间通讯的重要介质，可传递诸如微小核糖核酸（microRNA）、蛋白质和脂质等多种生物成分。外泌体在NAFLD疾病进展过程中肝细胞与巨噬细胞之间相互作用中的作用尚待探究。在本研究中，我们报告称，脂毒性损伤诱导富含miR - 192 - 5p的肝细胞外泌体释放，这在M1巨噬细胞激活和肝脏炎症中发挥了关键作用。NAFLD患者血清中的miR - 192 - 5p水平与肝脏炎症活动评分及疾病进展呈正相关。同样，在高脂高胆固醇饮食（HFHCD）喂养的大鼠模型中，血清miR - 192 - 5p水平、M1巨噬细胞数量以及肝脏促炎介质的表达水平均与疾病进展相关。脂毒性肝细胞比对照组释放更多富含miR - 192 - 5p的外泌体，这诱导了M1巨噬细胞（CD11b + CD86 + ）的激活以及诱导型一氧化氮合酶（iNOS）、白细胞介素 - 6（IL - 6）和肿瘤坏死因子 - α（TNF - α）表达的增加。此外，源自肝细胞的外泌体miR - 192 - 5p抑制了雷帕霉素靶蛋白（mTOR）的雷帕霉素不敏感伴侣蛋白（Rictor）的蛋白表达，进而抑制了蛋白激酶B（Akt）和叉头框转录因子O1（FoxO1）的磷酸化水平，导致FoxO1的激活以及随后炎症反应的诱导。结论：源自肝细胞的外泌体miR - 192 - 5p通过调节Rictor/Akt/FoxO1信号通路，在促炎巨噬细胞激活和NAFLD疾病进展中发挥关键作用。血清外泌体miR - 192 - 5p是潜在的非侵入性生物标志物以及非酒精性脂肪性肝炎的治疗靶点。
Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs, proteins, and lipids. The role of exosomes in cross-talk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored. In the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192–5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192–5p levels in NAFLD patients positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192–5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in the high-fat high-cholesterol diet (HFHCD)-fed rat models. Lipotoxic hepatocytes released more miR-192–5p-enriched exosomes than controls, which induced M1 macrophage (CD11b+CD86+) activation and increase of iNOS, IL-6, and TNF-α expression. Furthermore, hepatocyte-derived exosomal miR-192–5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in the activation of FoxO1 and subsequent induction of the inflammatory response. Conclusion: Hepatocyte-derived exosomal miR-192–5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD via modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192–5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.
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影响因子：
16.6
作者：
Hallowell RW;Collins SL;Craig JM;Zhang Y;Oh M;Illei PB;Chan-Li Y;Vigeland CL;Mitzner W;Scott AL;Powell JD;Horton MR
通讯作者：
Horton MR
DOI：
10.1002/wrna.1413
发表时间：
2017-07
期刊：
Wiley interdisciplinary reviews. RNA
影响因子：
--
作者：
Kim KM;Abdelmohsen K;Mustapic M;Kapogiannis D;Gorospe M
通讯作者：
Gorospe M
DOI：
10.1016/j.bbrc.2018.12.180
发表时间：
2019-02-12
影响因子：
3.1
作者：
Chen, Yu;Sun, Huanhuan;Zhi, Fachao
通讯作者：
Zhi, Fachao
miR-192的下调通过诱导SREBF1导致肝脏脂肪变性和脂质积累：双酚A引发的非酒精性脂肪肝的新机制
DOI：
10.1016/j.bbalip.2017.05.001
发表时间：
2017-09-01
影响因子：
4.8
作者：
Lin, Yi;Ding, Dongxiao;Dong, Sijun
通讯作者：
Dong, Sijun
影响因子：
25.7
作者：
Sato K;Meng F;Glaser S;Alpini G
通讯作者：
Alpini G