NOX4相关信号通路在肝纤维化发病机制中的作用
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摘要
还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NOX)是一种多蛋白质亚基组成的复合体,是活性氧簇(ROS)生成的主要酶类。现已证实NOXs介导的氧化应激与肝纤维化的发生发展密切相关,而其亚基NOX4则起了关键作用,其生成的ROS不仅能直接对引起肝纤维化的主要细胞?肝星状细胞(HSCs)具有显著的活化效应,还可通过介导包括HSCs在内的多种细胞内的信号传导通路参与HSCs的持续激活、细胞外基质的异常增殖、肝细胞的凋亡及肌成纤维细胞的迁移等过程,最终诱导肝纤维化的发生与发展。文章就NOX4相关信号通路在肝纤维化发病机制中的作用进行综述。
Reduced nicotinamide adenine dinucleotide phosphate oxidase(NDAPH oxidase,NOX)is a complex composed of multiple protein subunits and the main enzyme produced by reactive oxygen species(ROS). It has been confirmed that NOXs-mediated oxidative stress is closely related to the occurrence and development of liver fibrosis,and its subunit NOX4 plays a key role. Nox4-derived ROS can not only directly affect the main cell of liver fibrosis ells(HSCs)with significant activation effects but also participate in the continuous activation of HSCs,abnormal proliferation of extracellular matrices(ECMs),apoptosis of hepatocytes,and migration of myofibroblasts(MFBs)by mediating a variety of intracellular signaling pathways including HSCs,which ultimately lead to the occurrence and development of liver fibrosis. This article reviews the role of NOX4-related signaling pathways in the pathogenesis of hepatic fibrosis.
Reduced nicotinamide adenine dinucleotide phosphate oxidase(NDAPH oxidase,NOX)is a complex composed of multiple protein subunits and the main enzyme produced by reactive oxygen species(ROS). It has been confirmed that NOXs-mediated oxidative stress is closely related to the occurrence and development of liver fibrosis,and its subunit NOX4 plays a key role. Nox4-derived ROS can not only directly affect the main cell of liver fibrosis ells(HSCs)with significant activation effects but also participate in the continuous activation of HSCs,abnormal proliferation of extracellular matrices(ECMs),apoptosis of hepatocytes,and migration of myofibroblasts(MFBs)by mediating a variety of intracellular signaling pathways including HSCs,which ultimately lead to the occurrence and development of liver fibrosis. This article reviews the role of NOX4-related signaling pathways in the pathogenesis of hepatic fibrosis.
引文
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[5]Liang S,Kisseleva T,Brenner DA.The Role of NADPH Oxidases(NOXs)in Liver Fibrosis and the Activation of Myofibroblasts[J].Front Physiol,2016,7:17.
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[7]Gao HM,Zhou H,Hong JS.NADPH oxidases:novel therapeutic targets for neurodegenerative diseases[J].Trends Pharmacol Sci,2012,33(6):295-303.
[8]Jiang JX,Chen X,Serizawa N,et al.Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831,a novel NOX4/NOX1 inhibitor in vivo[J].Free Radic Biol Med,2012,53(2):289-296.
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[10]Zhang LL,Huang S,Ma XX,et al.Angiotensin(1-7)attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1beta/Smad circuit[J].Free Radic Biol Med,2016,97:531-543.
[11]Shimomura Y,Takaki A,Wada N,et al.The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma[J].Intern Med,2017,56(3):243-251.
[12]Panday A,Sahoo MK,Osorio D,et al.NADPH oxidases:an overview from structure to innate immunity-associated pathologies[J].Cell Mol Immunol,2015,12(1):5-23.
[13]Torok NJ.Dysregulation of redox pathways in liver fibrosis[J].Am J Physiol Gastrointest Liver Physiol,2016,311(4):G667-G674.
[14]Paik YH,Kim J,Aoyama T,et al.Role of NADPH oxidases in liver fibrosis[J].Antioxid Redox Signal,2014,20(17):2854-2872.
[15]Weyemi U,Dupuy C.The emerging role of ROS-generating NADPH oxidase NOX4 in DNA-damage responses[J].Mutat Res,2012,751(2):77-81.
[16]Wynn TA.Integrating mechanisms of pulmonary fibrosis[J].JExp Med,2011,208(7):1339-1350.
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[21]Altenhofer S,Kleikers PW,Radermacher KA,et al.The NOXtoolbox:validating the role of NADPH oxidases in physiology and disease[J].Cell Mol Life Sci,2012,69(14):2327-2343.
[22]陈艳军,张艳杰,关大勇,等.高山红景天对肝纤维化大鼠Smad_3 mRNA表达的影响[J].医学研究生学报,2012,25(12):1242-1246.
[23]Carmona-Cuenca I,Roncero C,Sancho P,et al.Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity[J].J Hepatol,2008,49(6):965-976.
[24]Pan X,Dai Y,Li X,et al.Inhibition of arsenic-induced rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-beta/Smad activation[J].Toxicol Appl Pharmacol,2011,254(3):323-331.
[25]Sancho P,Mainez J,Crosas-Molist E,et al.NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development[J].PLoS One,2012,7(9):e45285.
[26]Ikeda R,Ishii K,Hoshikawa Y,et al.Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor beta1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation[J].Inflamm Res,2011,60(6):597-604.
[27]Kawasaki T,Kawai T.Toll-like receptor signaling pathways[J].Front Immunol,2014,5:461.
[28]Singh A,Koduru B,Carlisle C,et al.NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Tolllike receptor-4[J].Sci Rep,2017,7(1):14346.
[29]Sun H,Chen G,Wen B,et al.Oligo-peptide I-C-F-6 inhibits hepatic stellate cell activation and ameliorates CCl4-induced liver fibrosis by suppressing NF-kappaB signaling and Wnt/betacatenin signaling[J].J Pharmacol Sci,2018,136(3):133-141.
[30]Xu H,Zhang S,Pan X,et al.TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway[J].Int Immunopharmacol,2016,38:233-237.
[31]Bataller R,Schwabe RF,Choi YH,et al.NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis[J].J Clin Invest,2003,112(9):1383-1394.
[32]Park HS,Jung HY,Park EY,et al.Cutting edge:direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B[J].J Immunol,2004,173(6):3589-3593.
[33]Zhao W,Ma G,Chen X.Lipopolysaccharide induced LOX-1expression via TLR4/MyD88/ROS activated p38MAPK-NF-kappaB pathway[J].Vascul Pharmacol,2014,63(3):162-172.
[34]黄晨恺,何丛,朱萱.炎症小体活化与非病毒性肝病的研究进展[J].医学研究生学报,2017,30(5):546-550.
[35]Strowig T,Henao-Mejia J,Elinav E,et al.Inflammasomes in health and disease[J].Nature,2012,481(7381):278-286.
[36]Wen H,Gris D,Lei Y,et al.Fatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signaling[J].Nat Immunol,2011,12(5):408-415.
[37]Wang W,Wu QH,Sui Y,et al.Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome[J].Biomed Pharmacother,2017,86:32-40.
[38]Liu Z,Tu K,Wang Y,et al.Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress,Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling[J].Cell Physiol Biochem,2017,44(5):1856-1868.
[39]Li J,Pan Y,Kan M,et al.Hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase[J].Life Sci,2014,98(1):24-30.
[40]Silva I,Rausch V,Peccerella T,et al.Hypoxia enhances H2O2-mediated upregulation of hepcidin:Evidence for NOX4-mediated iron regulation[J].Redox Biol,2018,16:1-10.
[41]Casu C,Nemeth E,Rivella S.Hepcidin agonists as therapeutic tools[J].Blood,2018,131(16):1790-1794.
[42]Yu JH,Zhu BM,Riedlinger G,et al.The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PU-MA and BIM in mice[J].Hepatology,2012,56(6):2375-2386.
[2]张洪,向述天.CT在肝纤维化及肝硬化诊断中的研究进展[J].医学研究生学报,2016,29(5):546-550.
[3]Sancho P,Mainez J,Crosas-Molist E,et al.NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development[J].PLoS One,2012,7(9):e45285.
[4]Yu SS,Chen B,Huang CK,et al.Ursolic acid suppresses TGF-beta1-induced quiescent HSC activation and transformation by inhibiting NADPH oxidase expression and Hedgehog signaling[J].Exp Ther Med,2017,14(4):3577-3582.
[5]Liang S,Kisseleva T,Brenner DA.The Role of NADPH Oxidases(NOXs)in Liver Fibrosis and the Activation of Myofibroblasts[J].Front Physiol,2016,7:17.
[6]Yu SS,Chen B,Huang CK,et al.Ursolic acid suppresses TGF-beta1-induced quiescent HSC activation and transformation by inhibiting NADPH oxidase expression and Hedgehog signaling[J].Exp Ther Med,2017,14(4):3577-3582.
[7]Gao HM,Zhou H,Hong JS.NADPH oxidases:novel therapeutic targets for neurodegenerative diseases[J].Trends Pharmacol Sci,2012,33(6):295-303.
[8]Jiang JX,Chen X,Serizawa N,et al.Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831,a novel NOX4/NOX1 inhibitor in vivo[J].Free Radic Biol Med,2012,53(2):289-296.
[9]Sancho P,Mainez J,Crosas-Molist E,et al.NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development[J].PLoS One,2012,7(9):e45285.
[10]Zhang LL,Huang S,Ma XX,et al.Angiotensin(1-7)attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1beta/Smad circuit[J].Free Radic Biol Med,2016,97:531-543.
[11]Shimomura Y,Takaki A,Wada N,et al.The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma[J].Intern Med,2017,56(3):243-251.
[12]Panday A,Sahoo MK,Osorio D,et al.NADPH oxidases:an overview from structure to innate immunity-associated pathologies[J].Cell Mol Immunol,2015,12(1):5-23.
[13]Torok NJ.Dysregulation of redox pathways in liver fibrosis[J].Am J Physiol Gastrointest Liver Physiol,2016,311(4):G667-G674.
[14]Paik YH,Kim J,Aoyama T,et al.Role of NADPH oxidases in liver fibrosis[J].Antioxid Redox Signal,2014,20(17):2854-2872.
[15]Weyemi U,Dupuy C.The emerging role of ROS-generating NADPH oxidase NOX4 in DNA-damage responses[J].Mutat Res,2012,751(2):77-81.
[16]Wynn TA.Integrating mechanisms of pulmonary fibrosis[J].JExp Med,2011,208(7):1339-1350.
[17]Cao Q,Mak KM,Lieber CS.Leptin represses matrix metalloproteinase-1 gene expression in LX2 human hepatic stellate cells[J].J Hepatol,2007,46(1):124-133.
[18]Jung JS,Ahn YH,Moon BI,et al.Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells[J].Int J Mol Sci,2016,17(4):477.
[19]Moon JS,Nakahira K,Chung KP,et al.NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages[J].Nat Med,2016,22(9):1002-1012.
[20]Lan T,Kisseleva T,Brenner DA.Deficiency of NOX1 or NOX4Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation[J].PLoS One,2015,10(7):e129743.
[21]Altenhofer S,Kleikers PW,Radermacher KA,et al.The NOXtoolbox:validating the role of NADPH oxidases in physiology and disease[J].Cell Mol Life Sci,2012,69(14):2327-2343.
[22]陈艳军,张艳杰,关大勇,等.高山红景天对肝纤维化大鼠Smad_3 mRNA表达的影响[J].医学研究生学报,2012,25(12):1242-1246.
[23]Carmona-Cuenca I,Roncero C,Sancho P,et al.Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity[J].J Hepatol,2008,49(6):965-976.
[24]Pan X,Dai Y,Li X,et al.Inhibition of arsenic-induced rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-beta/Smad activation[J].Toxicol Appl Pharmacol,2011,254(3):323-331.
[25]Sancho P,Mainez J,Crosas-Molist E,et al.NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development[J].PLoS One,2012,7(9):e45285.
[26]Ikeda R,Ishii K,Hoshikawa Y,et al.Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor beta1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation[J].Inflamm Res,2011,60(6):597-604.
[27]Kawasaki T,Kawai T.Toll-like receptor signaling pathways[J].Front Immunol,2014,5:461.
[28]Singh A,Koduru B,Carlisle C,et al.NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Tolllike receptor-4[J].Sci Rep,2017,7(1):14346.
[29]Sun H,Chen G,Wen B,et al.Oligo-peptide I-C-F-6 inhibits hepatic stellate cell activation and ameliorates CCl4-induced liver fibrosis by suppressing NF-kappaB signaling and Wnt/betacatenin signaling[J].J Pharmacol Sci,2018,136(3):133-141.
[30]Xu H,Zhang S,Pan X,et al.TIMP-1 expression induced by IL-32 is mediated through activation of AP-1 signal pathway[J].Int Immunopharmacol,2016,38:233-237.
[31]Bataller R,Schwabe RF,Choi YH,et al.NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis[J].J Clin Invest,2003,112(9):1383-1394.
[32]Park HS,Jung HY,Park EY,et al.Cutting edge:direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B[J].J Immunol,2004,173(6):3589-3593.
[33]Zhao W,Ma G,Chen X.Lipopolysaccharide induced LOX-1expression via TLR4/MyD88/ROS activated p38MAPK-NF-kappaB pathway[J].Vascul Pharmacol,2014,63(3):162-172.
[34]黄晨恺,何丛,朱萱.炎症小体活化与非病毒性肝病的研究进展[J].医学研究生学报,2017,30(5):546-550.
[35]Strowig T,Henao-Mejia J,Elinav E,et al.Inflammasomes in health and disease[J].Nature,2012,481(7381):278-286.
[36]Wen H,Gris D,Lei Y,et al.Fatty acid-induced NLRP3-ASCinflammasome activation interferes with insulin signaling[J].Nat Immunol,2011,12(5):408-415.
[37]Wang W,Wu QH,Sui Y,et al.Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome[J].Biomed Pharmacother,2017,86:32-40.
[38]Liu Z,Tu K,Wang Y,et al.Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress,Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling[J].Cell Physiol Biochem,2017,44(5):1856-1868.
[39]Li J,Pan Y,Kan M,et al.Hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase[J].Life Sci,2014,98(1):24-30.
[40]Silva I,Rausch V,Peccerella T,et al.Hypoxia enhances H2O2-mediated upregulation of hepcidin:Evidence for NOX4-mediated iron regulation[J].Redox Biol,2018,16:1-10.
[41]Casu C,Nemeth E,Rivella S.Hepcidin agonists as therapeutic tools[J].Blood,2018,131(16):1790-1794.
[42]Yu JH,Zhu BM,Riedlinger G,et al.The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PU-MA and BIM in mice[J].Hepatology,2012,56(6):2375-2386.