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Hippo/YAP参与肝纤维化发生发展的作用机制

赵晓璐 张春艳 高晓阳 马月宏

引用本文:
Citation:

Hippo/YAP参与肝纤维化发生发展的作用机制

DOI: 10.3969/j.issn.1001-5256.2022.07.037
基金项目: 

国家自然科学基金 (81960759);

国家自然科学基金 (81560706);

内蒙古自治区自然科学基金资助项目 (2019MS08010);

内蒙古自治区自然科学基金资助项目 (2014MS0841);

内蒙古自治区草原英才培养计划 ;

内蒙古自治区教坛新秀培养计划 ;

内蒙古医科大学致远人才计划项目 

利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:赵晓璐负责选题,总结文献,撰写文章; 张春艳、高晓阳负责查阅文献; 马月宏负责校正并最后定稿。
详细信息
    通信作者:

    马月宏,myh19982002@sina.com

Mechanism of action of the Hippo/YAP pathway in the development and progression of liver fibrosis

Research funding: 

National Natural Science Foundation of China (81960759);

National Natural Science Foundation of China (81560706);

Natural Science Foundation of Inner Mongolia Autonomous Region (2019MS08010);

Natural Science Foundation of Inner Mongolia Autonomous Region (2014MS0841);

Inner Mongolia Autonomous Region Grassland Talents Training Program ;

Inner Mongolia Autonomous Region Teaching Rookie Training Program ;

Inner Mongolia Medical University Zhiyuan Talent Program 

More Information
  • 摘要: 多种病因引起肝脏微环境的破坏而致肝组织结构功能丧失,启动肝纤维化进程,主要以肝星状细胞(HSC)活化为肌成纤维细胞, 分泌大量以胶原为主的细胞外基质(ECM)为特征表现。虽然目前对抗肝纤维化机制的研究已有很多,但仍缺乏有效的靶点药物应用于临床,近年来关于抗肝纤维化的研究多集中在肝纤维化进展期的干预,而忽略了早期肝纤维化的具体机制如何。最近关于Hippo信号在肝纤维化中的研究逐渐增多,集中于核心转录因子Yes相关蛋白(YAP)在早期活化HSC中的表达,及该通路调控HSC的状态,本文主要介绍了Hippo/YAP通路参与调控肝纤维化早期及进展期的作用,简述了调控核心因子YAP的稳定表达与核转位可逆转肝纤维化的潜在作用,表明了该通路可为临床治疗提供新的方向及靶点。

     

  • [1] SHAN L, LIU Z, CI L, et al. Research progress on the anti-hepatic fibrosis action and mechanism of natural products[J]. Int Immunopharmacol, 2019, 75: 105765. DOI: 10.1016/j.intimp.2019.105765.
    [2] WANG J, CEN P, CHEN J, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure[J]. Stem Cell Res Ther, 2017, 8(1): 137. DOI: 10.1186/s13287-017-0576-4.
    [3] MA S, MENG Z, CHEN R, et al. The Hippo pathway: biology and pathophysiology[J]. Annu Rev Biochem, 2019, 88: 577-604. DOI: 10.1146/annurev-biochem-013118-111829.
    [4] MENG Z, MOROISHI T, GUAN KL. Mechanisms of Hippo pathway regulation[J]. Genes Dev, 2016, 30(1): 1-17. DOI: 10.1101/gad.274027.115.
    [5] OU C, SUN Z, LI S, et al. Dual roles of yes-associated protein (YAP) in colorectal cancer[J]. Oncotarget, 2017, 8(43): 75727-75741. DOI: 10.18632/oncotarget.20155.
    [6] MOYA IM, HALDER G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine[J]. Nat Rev Mol Cell Biol, 2019, 20(4): 211-226. DOI: 10.1038/s41580-018-0086-y.
    [7] SHI X, ZHU HR, LIU TT, et al. The Hippo pathway in hepatocellular carcinoma: Non-coding RNAs in action[J]. Cancer Lett, 2017, 400: 175-182. DOI: 10.1016/j.canlet.2017.04.032.
    [8] PANCIERA T, AZZOLIN L, CORDENONSI M, et al. Mechanobiology of YAP and TAZ in physiology and disease[J]. Nat Rev Mol Cell Biol, 2017, 18(12): 758-770. DOI: 10.1038/nrm.2017.87.
    [9] LIU Q, LIU X, SONG G. The Hippo pathway: a master regulatory network important in cancer[J]. Cells, 2021, 10(6): 1416. DOI: 10.3390/cells10061416.
    [10] CHUNG SI, MOON H, KIM DY, et al. Development of a transgenic mouse model of hepatocellular carcinoma with a liver fibrosis background[J]. BMC Gastroenterol, 2016, 16: 13. DOI: 10.1186/s12876-016-0423-6.
    [11] MANNAERTS I, LEITE SB, VERHULST S, et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation[J]. J Hepatol, 2015, 63(3): 679-688. DOI: 10.1016/j.jhep.2015.04.011.
    [12] FRIEDMAN SL. Mechanisms of hepatic fibrogenesis[J]. Gastroenterology, 2008, 134(6): 1655-1669. DOI: 10.1053/j.gastro.2008.03.003.
    [13] KONISHI T, SCHUSTER RM, LENTSCH AB. Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury[J]. Am J Physiol Gastrointest Liver Physiol, 2018, 314(4): G471-G482. DOI: 10.1152/ajpgi.00153.2017.
    [14] LEE DH, PARK JO, KIM TS, et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development[J]. Nat Commun, 2016, 7: 11961. DOI: 10.1038/ncomms11961.
    [15] ZHAO W, ZHANG X, HOU M, et al. Traditional Chinese medicine Yiqi Huoxue recipe attenuates hepatic fibrosis via YAP/TAZ signaling[J]. Histol Histopathol, 2021, 36(9): 967-979. DOI: 10.14670/HH-18-373.
    [16] YANG T, CHEN XL, ZHU XY, et al. Solanum solanacene extract down-regulates YAP and TGFβ/Smad pathways to inhibit hepatic stellate cell activation and improve liver fibrosis in mice[J]. Acta Pharm Sin, 2021, 56(11): 2985-2994. DOI: 10.16438/j.0513-4870.2021-1185.

    杨挺, 陈馨霖, 祝小云, 等. 苦蘵睡茄内酯提取物下调YAP和TGFβ/Smad通路抑制肝星状细胞激活改善小鼠肝纤维化[J]. 药学学报, 2021, 56(11): 2985-2994. DOI: 10.16438/j.0513-4870.2021-1185.
    [17] LIU F, LAGARES D, CHOI KM, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308(4): L344-357. DOI: 10.1152/ajplung.00300.2014.
    [18] HAAK AJ, KOSTALLARI E, SICARD D, et al. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis[J]. Sci Transl Med, 2019, 11(516): eaau6296. DOI: 10.1126/scitranslmed.aau6296.
    [19] MARTIN K, PRITCHETT J, LLEWELLYN J, et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis[J]. Nat Commun, 2016, 7: 12502. DOI: 10.1038/ncomms12502.
    [20] FILLIOL A, SCHWABE RF. Contributions of fibroblasts, extracellular matrix, stiffness, and mechanosensing to hepatocarcinogenesis[J]. Semin Liver Dis, 2019, 39(3): 315-333. DOI: 10.1055/s-0039-1685539.
    [21] LAU LF. Cell surface receptors for CCN proteins[J]. J Cell Commun Signal, 2016, 10(2): 121-127. DOI: 10.1007/s12079-016-0324-z.
    [22] O'HARA SP, LA RUSSO NF. Cellular senescence, neuropeptides and hepatic fibrosis: Additional insights into increasing complexity[J]. Hepatology, 2017, 66(2): 318-320. DOI: 10.1002/hep.29243.
    [23] LI H, HE F, ZHAO X, et al. YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-mitochondrial fission-HtrA2/Omi pathways[J]. Cell Physiol Biochem, 2017, 44(5): 2073-2089. DOI: 10.1159/000485946.
    [24] VARGA ZV, GIRICZ Z, LIAUDET L, et al. Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy[J]. Biochim Biophys Acta, 2015, 1852(2): 232-242. DOI: 10.1016/j.bbadis.2014.06.030.
    [25] LIU Y, LU T, ZHANG C, et al. Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury[J]. J Hepatol, 2019, 71(4): 719-730. DOI: 10.1016/j.jhep.2019.05.029.
    [26] YU HX, YAO Y, BU FT, et al. Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells[J]. Mol Immunol, 2019, 107: 29-40. DOI: 10.1016/j.molimm.2019.01.004.
    [27] KRIZHANOVSKY V, YON M, DICKINS RA, et al. Senescence of activated stellate cells limits liver fibrosis[J]. Cell, 2008, 134(4): 657-667. DOI: 10.1016/j.cell.2008.06.049.
    [28] JIN H, LIAN N, ZHANG F, et al. Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine[J]. Eur J Pharm Sci, 2017, 96: 323-333. DOI: 10.1016/j.ejps.2016.10.002.
    [29] ALSAMMAN S, CHRISTENSON SA, YU A, et al. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice[J]. Sci Transl Med, 2020, 12(557): eaay8798. DOI: 10.1126/scitranslmed.aay8798.
    [30] LIU-CHITTENDEN Y, HUANG B, SHIM JS, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP[J]. Genes Dev, 2012, 26(12): 1300-1305. DOI: 10.1101/gad.192856.112.
    [31] CHEN YJ, HAO P, DAI YJ, et al. Improve liver fibrosis of the liver-specific knockout of Yes associated protein through antioxidant effects in mice[J]. Chin J Clin Pharmacol, 2021, 37(17): 4. DOI: 10.13699/j.cnki.1001-6821.2021.17.017.

    陈雅静, 郝鹏, 代玉娇, 等. 肝特异性敲除Yes相关蛋白基因可通过抗氧化作用改善小鼠的肝纤维化[J]. 中国临床药理学杂志, 2021, 37(17): 4. DOI: 10.13699/j.cnki.1001-6821.2021.17.017.
    [32] LI C, ZHANG R, ZHAN Y, et al. Resveratrol inhibits hepatic stellate cell activation via the Hippo pathway[J]. Mediators Inflamm, 2021, 2021: 3399357. DOI: 10.1155/2021/3399357.
    [33] ZHANG K, CHANG Y, SHI Z, et al. ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation[J]. Sci Rep, 2016, 6: 30029. DOI: 10.1038/srep30029.
    [34] MOHSENI R, KARIMI J, TAVILANI H, et al. Carvacrol ameliorates the progression of liver fibrosis through targeting of Hippo and TGFβ signaling pathways in carbon tetrachloride (CCl4)-induced liver fibrosis in rats[J]. Immunopharmacol Immunotoxicol, 2019, 41(1): 163-171. DOI: 10.1080/08923973.2019.1566926.
    [35] NIU WX, CHEN MH, ZHANG N, et al. Pepstatin Pr shows its anti-liver fibrosis effect in vitro through YAP-TGFβ-Smad pathway[J]. Acta Pharm Sin, 2019, 54(1): 89-94. DOI: 10.16438/j.0513-4870.2018-0705.

    牛伟晓, 陈明华, 张娜, 等. Pepstatin Pr通过YAP-TGFβ-Smad通路发挥体外抗肝纤维化作用[J]. 药学学报, 2019, 54(1): 89-94. DOI: 10.16438/j.0513-4870.2018-0705.
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  • 收稿日期:  2021-12-13
  • 录用日期:  2022-01-13
  • 出版日期:  2022-07-20
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