中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Role of FOXO1/3 in the pathogenesis of hepatic fibrosis

DOI: 10.3969/j.issn.1001-5256.2019.08.043
Research funding:

 

  • Received Date: 2019-01-28
  • Published Date: 2019-08-20
  • Hepatic fibrosis refers to the pathological process of abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. Hepatic fibrosis is observed in the whole process of liver injury repair and healing, and long-term chronic injury factors may induce the progression of hepatic fibrosis into liver cirrhosis. Epidemiological data show that there are 1. 1805 million new cases of hepatitis B and 243 thousand cases of hepatitis C reported in 2017. Chronic viral hepatitis has brought heavy social and economic burden. Forkhead transcription factor (FOXO) belongs to the forkhead family and plays an important role in various cell life activities. Studies have shown that FOXO1/3 can regulate hepatic stellate cell activity through the TGFβ pathway and thus play an important role in hepatic fibrosis. This article reviews the research advances in the pathogenesis of hepatic fibrosis, the mechanism of action of FOXO1/3 in the regulation of hepatic fibrosis, and targeted therapy for FOXO1/3 (one of the sites for hepatic fibrosis) .

     

  • [1] BULLOCK M. FOXO factors and breast cancer:Outfoxing endocrine resistance[J]. Endocr Relat Cancer, 2016, 23 (2) :113-130.
    [2] WEIGEL D, JURGENS G, KUTTNER F, et al. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo[J]. Cell, 1989, 57 (4) :645-658.
    [3] KUMAZOE M, TAKAI M, BAE J, et al. FOXO3 is essential for CD44 expression in pancreatic cancer cells[J]. Oncogene, 2017, 36 (19) :2643-2654.
    [4] WILHELM K, HAPPEL K, EELEN G, et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium[J]. Nature, 2016, 529 (7585) :216-220.
    [5] DAS SK, DESAULNIERS J, DYCK JR, et al. Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload[J]. Liver Int, 2016, 36 (2) :246-257.
    [6] de MAGALHAES JP, WUTTKE D, WOOD SH, et al. Genomeenvironment interactions that modulate aging:Powerful targets for drug discovery[J]. Pharmacol Rev, 2012, 64 (1) :88-101.
    [7] SALMINEN A, KAARNIRANTA K, KAUPPINEN A. Age-related changes in AMPK activation:Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways[J]. Ageing Res Rev, 2016, 28:15-26.
    [8] NANTHAKUMAR CB, HATLEY RJ, LEMMA S, et al. Dissecting fibrosis:Therapeutic insights from the small-molecule toolbox[J]. Nat Rev Drug Discov, 2015, 14 (10) :693-720.
    [9] ROCKEY DC, BELL PD, HILL JA. Fibrosis—a common pathway to organ injury and failure[J]. N Engl J Med, 2015, 372 (12) :1138-1149.
    [10] 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.
    [11] GRESSNER OA, RIZK MS, KOVALENKO E, et al. Changing the pathogenetic roadmap of liver fibrosis? Where did it start;where will it go?[J]. J Gastroenterol Hepatol, 2008, 23 (7 Pt1) :1024-1035.
    [12] LI Y, LU LG. Molecular basis of hepatic fibrosis and current status of its diagnosis and treatment[J]. J Clin Hepatol, 2018, 34 (1) :12-15. (in Chinese) 李妍, 陆伦根.肝纤维化的分子基础与临床诊治现状[J].临床肝胆病杂志, 2018, 34 (1) :12-15.
    [13] ZHANG W, JIA JD. Pathogenesis and new therapeutic targets of liver fibrosis[J]. J Clin Hepatol, 2017, 33 (3) :409-412. (in Chinese) 张伟, 贾继东.肝纤维化的发病机制及治疗新靶点[J].临床肝胆病杂志, 2017, 33 (3) :409-412.
    [14] SAITO I, SARUTA T. Therapeutic drug monitoring of inhibitors of renin-angiotensin system[J]. Nihon Rinsho, 1990, 48 (Suppl) :1146-1148.
    [15] BENTEN D, KUMARAN V, JOSEPH B, et al. Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat[J]. Hepatology, 2005, 42 (5) :1072-1081.
    [16] XU MY, HU JJ, SHEN J, et al. Stat3 signaling activation crosslinking of TGF-beta1 in hepatic stellate cell exacerbates liver injury and fibrosis[J]. Biochim Biophys Acta, 2014, 1842 (11) :2237-2245.
    [17] CAI W, ZHAO L, LI HR, et al. Influence of kaempferol on TGF-beta1/Smads signal path in liver tissue of mice with Schistosoma japonicum infection[J]. Chin J Schi Contl, 2014, 26 (4) :399-404, 419. (in Chinese) 蔡文, 赵雷, 李华蓉, 等.山奈酚对感染日本血吸虫小鼠TGF-β1/Smads信号通路的影响[J].中国血吸虫病防治杂志, 2014, 26 (4) :399-404, 419.
    [18] CUTRONEO KR. TGF-beta-induced fibrosis and SMAD signaling:Oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring[J]. Wound Repair Regen, 2007, 15 (Suppl 1) :s54-s60.
    [19] HEMMANN S, GRAF J, RODERFELD M, et al. Expression of MMPs and TIMPs in liver fibrosis-a systematic review with special emphasis on anti-fibrotic strategies[J]. J Hepatol, 2007, 46 (5) :955-975.
    [20] BREW K, NAGASE H. The tissue inhibitors of metalloproteinases (TIMPs) :An ancient family with structural and functional diversity[J]. Biochim Biophys Acta, 2010, 1803 (1) :55-71.
    [21] RAMIREZ T, LI YM, YIN S, et al. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression[J]. J Hepatol, 2017, 66 (3) :601-609.
    [22] WU X, WU X, MA Y, et al. CUG-binding protein 1 regulates HSC activation and liver fibrogenesis[J]. Nat Commun, 2016, 7:13498.
    [23] LAINE F, RUIVARD M, LOUSTAUD-RATTI V, et al. Metabolic and hepatic effects of bloodletting in dysmetabolic iron overload syndrome:A randomized controlled study in 274 patients[J]. Hepatology, 2017, 65 (2) :465-474.
    [24] DAS SK, DESAULNIERS J, DYCK JR, et al. Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload[J]. Liver Int, 2016, 36 (2) :246-257.
    [25] HUANG CK, YU T, de la MONTE SM, et al. Restoration of Wnt/beta-catenin signaling attenuates alcoholic liver disease progression in a rat model[J]. J Hepatol, 2015, 63 (1) :191-198.
    [26] PASSINO MA, ADAMS RA, SIKORSKI SL, et al. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR[J]. Science, 2007, 315 (5820) :1853-1856.
    [27] LOPEZ-SANCHEZ I, DUNKEL Y, ROH YS, et al. GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis[J]. Nat Commun, 2014, 5:4451.
    [28] ADACHI M, OSAWA Y, UCHINAMI H, et al. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells[J]. Gastroenterology, 2007, 132 (4) :1434-1446.
    [29] LI A, WANG J, WU M, et al. The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1phase cell cycle arrest:Persistent p27 (Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway[J]. Eur J Pharmacol, 2015, 747:71-87.
    [30] MICHEAU O. Cellular FLICE-inhibitory protein:An attractive therapeutic target?[J]. Expert Opin Ther Targets, 2003, 7 (4) :559-573.
    [31] PARK SJ, SOHN HY, YOON J, et al. Down-regulation of FoxO-dependent c-FLIP expression mediates TRAIL-induced apoptosis in activated hepatic stellate cells[J]. Cell Signal, 2009, 21 (10) :1495-1503.
    [32] DURAN A, HERNANDEZ ED, REINA-CAMPOS M, et al.p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer[J]. Cancer Cell, 2016, 30 (4) :595-609.
    [33] GOURDIE RG, DIMMELER S, KOHL P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease[J]. Nat Rev Drug Discov, 2016, 15 (9) :620-638.
    [34] ADACHI M, OSAWA Y, UCHINAMI H, et al. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells[J]. Gastroenterology, 2007, 132 (4) :1434-1446.
    [35] GAGGAR A, WEATHINGTON N. Bioactive extracellular matrix fragments in lung health and disease[J]. J Clin Invest, 2016, 126 (9) :3176-3184.
    [36] CROSAS-MOLIST E, FABREGAT I. Role of NADPH oxidases in the redox biology of liver fibrosis[J]. Redox Biol, 2015, 6:106-111.
    [37] OZAKI I, HAMAJIMA H, MATSUHASHI S, et al. Regulation of TGF-beta1-induced pro-apoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver[J]. Front Physiol, 2011, 2:78.
    [38] DENG G, HUANG FZ, LIU XY, et al. Construction of recom binant adenovirus containing Akt and its expression in the liver of cirrhotic rats[J]. Chin J Gen Surg, 2008, 17 (7) :687-691. (in Chinese) 邓刚, 黄飞舟, 刘浔阳, 等.重组Akt腺病毒的构建及其在肝硬化大鼠肝脏中的表达[J].中国普通外科杂志, 2008, 17 (7) :687-691.
    [39] VALDERRAMA-CARVAJAL H, COCOLAKIS E, LACERTE A, et al. Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP[J]. Nat Cell Biol, 2002, 4 (12) :963-969.
    [40] KIM BC. FoxO3a mediates transforming growth factor-beta1-induced apoptosis in Fa O rat hepatoma cells[J]. BMB Rep, 2008, 41 (10) :728-732.
    [41] PIAO SG, KANG SH, LIM SW, et al. Influence of N-acetylcysteine on Klotho expression and its signaling pathway in experimental model of chronic cyclosporine nephropathy in mice[J]. Transplantation, 2013, 96 (2) :146-153.
    [42] BOSE SK, KIM H, MEYER K, et al. Forkhead box transcription factor regulation and lipid accumulation by hepatitis C virus[J]. J Virol, 2014, 88 (8) :4195-4203.
    [43] van den BORNE SW, DIEZ J, BLANKESTEIJN WM, et al. Myocardial remodeling after infarction:The role of myofibroblasts[J]. Nat Rev Cardiol, 2010, 7 (1) :30-37.
    [44] PRABHU SD, FRANGOGIANNIS NG. The biological basis for cardiac repair after myocardial infarction:From inflammation to fibrosis[J]. Circ Res, 2016, 119 (1) :91-112.
    [45] MAZZOCCOLI G, de COSMO S, MAZZA T. The biological clock:A pivotal hub in non-alcoholic fatty liver disease pathogenesis[J]. Front Physiol, 2018, 9:193.
    [46] SHIRASAKI T, HONDA M, SHIMAKAMI T, et al. Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway[J]. Hepatology, 2014, 60 (5) :1519-1530.
    [47] HARIHARAN N, MAEJIMA Y, NAKAE J, et al. Deacetylation of Fox O by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes[J]. Circ Res, 2010, 107 (12) :1470-1482.
    [48] SENGUPTA A, MOLKENTIN JD, PAIK JH, et al. Fox O transcription factors promote cardiomyocyte survival upon induction of oxidative stress[J]. J Biol Chem, 2011, 286 (9) :7468-7478.
    [49] ZHANG K, LI L, QI Y, et al. Hepatic suppression of Foxo1and Foxo3 causes hypoglycemia and hyperlipidemia in mice[J]. Endocrinology, 2012, 153 (2) :631-646.
    [50] NAKAE J, CAO Y, OKI M, et al. Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure[J]. Diabetes, 2008, 57 (3) :563-576.
    [51] KAMEI Y, MIURA S, SUZUKI M, et al. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control[J]. J Biol Chem, 2004, 279 (39) :41114-41123.
    [52] MILAN G, ROMANELLO V, PESCATORE F, et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy[J]. Nat Commun, 2015, 6:6670.
  • Relative Articles

    [1]Yunchong WU, Yanyan YANG, Chuan LI, Xiaohuan WU, Shide LIN. Role of inflammatory cytokines in disorder of glucose metabolism in patients with liver cirrhosis[J]. Journal of Clinical Hepatology, 2024, 40(9): 1886-1890. doi: 10.12449/JCH240926
    [2]Zunlan ZHOU, Lina YANG, Qingqing LI, Hong WANG. Research advances in the early predictive factors for non-neoplastic portal vein thrombosis in liver cirrhosis[J]. Journal of Clinical Hepatology, 2022, 38(9): 2150-2154. doi: 10.3969/j.issn.1001-5256.2022.09.039
    [3]Huan WANG, Xiaoxu SHEN, Liangqi CHEN, Tianlan GONG. Association of JAK/STAT signaling pathway with portal vein thrombosis after splenectomy in cirrhotic patients with portal hypertension[J]. Journal of Clinical Hepatology, 2022, 38(10): 2260-2264. doi: 10.3969/j.issn.1001-5256.2022.10.012
    [4]Jie ZHOU, Yunhao HUA, Xiaomei WANG, Junqi NIU. Role of transcription factor Yin Yang 1 in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2022, 38(8): 1918-1922. doi: 10.3969/j.issn.1001-5256.2022.08.039
    [5]Qunli GU, Hui LI, Xiuxiu DENG, Zijian ZENG, Haijian DONG. Research advances in the association between activating transcription factor 3 and chronic liver diseases[J]. Journal of Clinical Hepatology, 2021, 37(9): 2236-2240. doi: 10.3969/j.issn.1001-5256.2021.09.047
    [6]Xiaoke RAN, Xinju CHEN, Yunxia ZHAO, Xin ZHANG, He YANG, Yiyao SUN, Xiaoqi CHEN. Expression and clinical significance of forkhead box A2 and forkhead box J2 in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2021, 37(6): 1342-1347. doi: 10.3969/j.issn.1001-5256.2021.06.025
    [7]Tianyu LI, Huimin YAN. Mechanism of action of forkhead box transcription factors in hepatocellular carcinoma and their prospects as treatment targets[J]. Journal of Clinical Hepatology, 2021, 37(4): 931-934. doi: 10.3969/j.issn.1001-5256.2021.04.044
    [8]Guo XiaoXia, Hu Na, Lian XiaoXiao, Sun YuanPei, Li YuZhen, Lu: Lei, Ye YongAn, Li XiaoKe. Features of intestinal flora imbalance in patients with liver cirrhosis and related driving factors[J]. Journal of Clinical Hepatology, 2020, 36(7): 1527-1533. doi: 10.3969/j.issn.1001-5256.2020.07.016
    [9]Kong Li, Jin Meng, Wang WeiZhen, Zhao SuXian, Wang ShanShan. The mRNA expression of TIPE2, Foxp3, and CTLA-4 in peripheral blood mononucleated cells in patients with chronic hepatitis C and their clinical significance[J]. Journal of Clinical Hepatology, 2019, 35(2): 323-327. doi: 10.3969/j.issn.1001-5256.2019.02.016
    [10]Zhou YiLong, Chen Yuan, Zhang YiXin, Shao BingFeng, Zhang SuQing, Xu AiBing, He Song, Li YongJun, Tian SiYuan. Influence of Forkhead box Q1 expression on therapeutic effect of transarterial chemoembolization after hepatocellular carcinoma surgery[J]. Journal of Clinical Hepatology, 2016, 32(11): 2126-2129. doi: 10.3969/j.issn.1001-5256.2016.11.024
    [11]Feng Jie, Tang ZhengHao, Yu YongSheng. Expression of transcription factor Sp1 in hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2013, 29(1): 65-67.
    [12]Nan YueMin, Mi HongMei, Du JingHua, Wang RongQi, Kong LingBo, Ren WeiGuang, Li Hui, Zhao SuXian. Role and molecular mechanism of HO-1-mediated NF-κB modulation in fibrosis progression of nonalcoholic steatohepatitis[J]. Journal of Clinical Hepatology, 2013, 29(5): 375-378.
    [13]Wei SiChen, Zheng GuoQi. Role of adipokine in the pathogenesis of cirrhosis of the liver[J]. Journal of Clinical Hepatology, 2012, 28(1): 78-81.
    [14]Zhang ZhiYong, Jin WuPi, Xu XiaoJun.

    Research progress of nuclear factor-kappa B and alcoholic liver disease

    [J]. Journal of Clinical Hepatology, 2010, 26(3): 269-271.
    [16]Huang JiLiang, Wu Fang, Zhang XinRan, Wang DongHua, Zhao RuiZhi. Relationship between tumor necrosis factor-α and lnsulin resistance in patients with liver cirrhosis[J]. Journal of Clinical Hepatology, 2002, 18(3): 166-167.
    [19]Zhu YingHua, Song HongLi, Zhang Yi, Yu Guang, Han JiJin. The Clinieal study about interleukin-1 and tumor necrosis factor Alpha in hepatocirrhosis[J]. Journal of Clinical Hepatology, 2001, 17(4): 233-234.
  • Cited by

    Periodical cited type(0)

    Other cited types(2)

  • 加载中
    Created with Highcharts 5.0.7Chart context menuAccess Class DistributionFULLTEXT: 4.7 %FULLTEXT: 4.7 %META: 89.6 %META: 89.6 %PDF: 5.7 %PDF: 5.7 %FULLTEXTMETAPDF
    Created with Highcharts 5.0.7Chart context menuAccess Area Distribution其他: 7.3 %其他: 7.3 %其他: 3.1 %其他: 3.1 %Canada: 0.5 %Canada: 0.5 %College Station: 0.5 %College Station: 0.5 %India: 0.2 %India: 0.2 %Kao-sung: 0.2 %Kao-sung: 0.2 %Malvern: 0.5 %Malvern: 0.5 %Russian Federation: 0.2 %Russian Federation: 0.2 %[]: 2.6 %[]: 2.6 %上海: 2.6 %上海: 2.6 %东京都: 0.2 %东京都: 0.2 %中山: 0.3 %中山: 0.3 %丽水: 0.5 %丽水: 0.5 %休斯顿: 0.2 %休斯顿: 0.2 %加利福尼亚州: 0.2 %加利福尼亚州: 0.2 %北京: 2.8 %北京: 2.8 %匹兹堡: 0.5 %匹兹堡: 0.5 %华城: 0.7 %华城: 0.7 %南京: 0.2 %南京: 0.2 %南宁: 0.2 %南宁: 0.2 %印第安纳波利斯: 0.5 %印第安纳波利斯: 0.5 %台州: 2.1 %台州: 2.1 %合肥: 0.2 %合肥: 0.2 %吉林: 0.2 %吉林: 0.2 %哥伦布: 0.2 %哥伦布: 0.2 %安條克: 0.2 %安條克: 0.2 %密蘇里城: 0.2 %密蘇里城: 0.2 %广州: 0.3 %广州: 0.3 %张家口: 3.0 %张家口: 3.0 %成都: 0.3 %成都: 0.3 %昆明: 0.7 %昆明: 0.7 %杭州: 1.2 %杭州: 1.2 %武汉: 1.0 %武汉: 1.0 %沈阳: 0.3 %沈阳: 0.3 %波士顿: 0.3 %波士顿: 0.3 %洛杉矶: 0.2 %洛杉矶: 0.2 %洛阳: 0.2 %洛阳: 0.2 %济南: 0.2 %济南: 0.2 %深圳: 0.2 %深圳: 0.2 %湖州: 1.2 %湖州: 1.2 %特洛伊: 0.2 %特洛伊: 0.2 %绍兴: 0.2 %绍兴: 0.2 %芒廷维尤: 28.0 %芒廷维尤: 28.0 %芝加哥: 0.5 %芝加哥: 0.5 %苏州: 0.2 %苏州: 0.2 %莫斯科: 1.0 %莫斯科: 1.0 %莱克朗兰比塞特尔: 0.2 %莱克朗兰比塞特尔: 0.2 %蚌埠: 0.3 %蚌埠: 0.3 %衢州: 0.7 %衢州: 0.7 %西宁: 28.3 %西宁: 28.3 %西安: 1.0 %西安: 1.0 %诺沃克: 0.2 %诺沃克: 0.2 %重庆: 0.2 %重庆: 0.2 %长春: 1.2 %长春: 1.2 %长沙: 0.3 %长沙: 0.3 %长治: 0.3 %长治: 0.3 %青岛: 0.2 %青岛: 0.2 %首尔特别: 0.7 %首尔特别: 0.7 %其他其他CanadaCollege StationIndiaKao-sungMalvernRussian Federation[]上海东京都中山丽水休斯顿加利福尼亚州北京匹兹堡华城南京南宁印第安纳波利斯台州合肥吉林哥伦布安條克密蘇里城广州张家口成都昆明杭州武汉沈阳波士顿洛杉矶洛阳济南深圳湖州特洛伊绍兴芒廷维尤芝加哥苏州莫斯科莱克朗兰比塞特尔蚌埠衢州西宁西安诺沃克重庆长春长沙长治青岛首尔特别

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 (1085) PDF downloads(218) Cited by(2)
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return