中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 7
Jul.  2022
Turn off MathJax
Article Contents

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

DOI: 10.3969/j.issn.1001-5256.2022.07.037
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
  • Corresponding author: MA Yuehong, myh19982002@sina.com(ORCID: 0000-0003-1414-0066)
  • Received Date: 2021-12-13
  • Accepted Date: 2022-01-13
  • Published Date: 2022-07-20
  • Various etiologies cause the destruction of liver microenvironment, which leads to the loss of liver structure and function and initiates the process of liver fibrosis. Hepatic stellate cells (HSCs) are mainly activated into myofibroblasts that secrete a large amount of extracellular matrix (ECM), mostly collagen. Although there have been many studies on the anti-liver fibrosis mechanism, there is still a lack of effective target drugs for clinical application, and in recent years, studies on anti-liver fibrosis have mainly focused on interventions for the advanced stage of liver fibrosis, while ignoring the specific mechanism of early-stage liver fibrosis. Recently, there have been an increasing number of studies on Hippo signaling in liver fibrosis, with a focus on the expression of the core transcription factor Yes-associated protein (YAP) in early activated HSCs and the regulation of HSC status by this pathway. This article mainly introduces the role of the Hippo/YAP pathway in the regulation of early-stage or advanced liver fibrosis and briefly describes the potential role of regulating the stable expression and nuclear translocation of the core transcription factor YAP in reversing liver fibrosis, suggesting that this pathway can provide new directions and targets for clinical treatment.

     

  • loading
  • [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.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (793) PDF downloads(73) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return