Liver knockout YAP gene improved insulin resistance-induced hepatic fibrosis

in Journal of Endocrinology
View More View Less
  • 1 School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China
  • 2 School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China
  • 3 Department of Pharmacy, North China University of Science and Technology, Tangshan, Hebei, China
  • 4 Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan, Hebei, China
  • 5 Tangshan Key Laboratory of Basic Research in Medicine Development, North China University of Science and Technology, Tangshan, Hebei, China

Correspondence should be addressed to Y Zhang or Y Qi: zhangyuxin@ncst.edu.cn or yajuanqi@ncst.edu.cn

*(Y Dai, P Hao and Z Sun contributed equally to this work)

Restricted access

Yes-associated protein (YAP), as a co-activator of transcription factors, is a downstream protein in the Hippo signaling pathway with important functions in cell proliferation, apoptosis, invasion and migration. YAP also plays a key role in the development of CCl4-induced liver fibrosis. However, the mechanism of YAP during hepatic fibrosis progression and reversion is still unclear. Mild liver fibrosis was developed after 4 months of high-fat diet (HFD) stimulation, and we found that the YAP signaling pathway was activated. Here, we aim to reveal whether specific knockout of Yap gene in the liver can improve liver fibrosis induced by insulin resistance (IR) stimulated by HFD, and further explain its specific mechanism. We found that liver-specific Yap gene knockout improved IR-induced liver fibrosis and liver dysfunction, and this mechanism is related to the inhibition of the insulin signal pathway at the FoxO1 level. These findings provide a new insight, and Yap is expected to be a new target to reverse the early stage of liver fibrosis induced by IR.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 189 189 189
Full Text Views 19 19 19
PDF Downloads 30 30 30
  • Åberg F, Helenius-Hietala J, Puukka P, Färkkilä M & Jula A 2018 Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. Hepatology 67 21412149. (https://doi.org/10.1002/hep.29631)

    • Search Google Scholar
    • Export Citation
  • Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD & Stahler A et al. 2015 Liver fibrosis, but no other histologic features, is associated with longterm outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149 389 .e1039 7.e10. (https://doi.org/10.1053/j.gastro.2015.04.043)

    • Search Google Scholar
    • Export Citation
  • Aydin MM & Akcali KC 2018 Liver fibrosis. Turkish Journal of Gastroenterology 29 1421. (https://doi.org/10.5152/tjg.2018.17330)

  • Bataller R & Brenner DA 2005 Liver fibrosis. Journal of Clinical Investigation 115 209218. (https://doi.org/10.1172/JCI24282)

  • Chen P, Luo Q, Huang C, Gao Q, Li L, Chen J, Chen B, Liu W, Zeng W & Chen Z 2018 Pathogenesis of non-alcoholic fatty liver disease mediated by YAP. Hepatology International 12 2636. (https://doi.org/10.1007/s12072-017-9841-y)

    • Search Google Scholar
    • Export Citation
  • Chen L, Su X & Hu Y 2020a Berberine down-regulated myostatin expression and facilitated metabolism via Smad pathway in insulin resistant mice. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 13 45614569. (https://doi.org/10.2147/DMSO.S275301)

    • Search Google Scholar
    • Export Citation
  • Chen Y, Li R, Hu N, Yu C, Song H, Li Y, Dai Y, Guo Z, Li M & Zheng Y et al. 2020b Baihe Wuyao decoction ameliorates CCl4-induced chronic liver injury and liver fibrosis in mice through blocking TGF-β1/Smad2/3 signaling, anti-inflammation and anti-oxidation effects. Journal of Ethnopharmacology 263 113227. (https://doi.org/10.1016/j.jep.2020.113227)

    • Search Google Scholar
    • Export Citation
  • Cinar B, Fang P-K & Freeman MR 2007 The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO Journal 31 45234534. (https://doi.org/10.1038/sj.emboj.7601872)

    • Search Google Scholar
    • Export Citation
  • Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O’Connor K, Galli GG, Yimlamai D & Chhangawala S 2016 Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nature Cell Biology 18 886896. (https://doi.org/10.1038/ncb3389)

    • Search Google Scholar
    • Export Citation
  • Dooley S & ten Dijke P 2012 TGF-beta in progression of liver disease. Cell and Tissue Research 347 245256. (https://doi.org/10.1007/s00441-011-1246-y)

    • Search Google Scholar
    • Export Citation
  • Feng R, Luo C, Li C, Du S, Okekunle AP, Li Y, Chen Y, Zi T & Niu Y 2017 Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case – control study. Lipids in Health and Disease 16 165. (https://doi.org/10.1186/s12944-017-0551-1)

    • Search Google Scholar
    • Export Citation
  • Friedman SL 2008a Mechanisms of hepatic fibrogenesis. Gastroenterology 134 16551669. (https://doi.org/10.1053/j.gastro.2008.03.003)

  • Friedman SL 2008b Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiological Reviews 88 125172. (https://doi.org/10.1152/physrev.00013.2007)

    • Search Google Scholar
    • Export Citation
  • Fruci B, Giuliano S, Mazza A, Malaguarnera R & Belfiore A 2013 Nonalcoholic Fatty liver: a possible new target for type 2 diabetes prevention and treatment. International Journal of Molecular Sciences 14 2293322966. (https://doi.org/10.3390/ijms141122933)

    • Search Google Scholar
    • Export Citation
  • Gaggini M, Carli F, Rosso C, Younes R, D’Aurizio R, Bugianesi E & Gastaldelli A 2019 Altered metabolic profile and adipocyte insulin resistance mark severe liver fibrosis in patients with chronic liver disease. International Journal of Molecular Sciences 20 6333. (https://doi.org/10.3390/ijms20246333)

    • Search Google Scholar
    • Export Citation
  • Geerts A 2001 History, heterogeneity, developmental biology and functions of quiescent hepatic stellate cells. Seminars in Liver Disease 21 311335. (https://doi.org/10.1055/s-2001-17550)

    • Search Google Scholar
    • Export Citation
  • Geisler F & Strazzabosco M 2015 Emerging roles of Notch signaling in liver disease. Hepatology 61 382392. (https://doi.org/10.1002/hep.27268)

    • Search Google Scholar
    • Export Citation
  • Glrizes PE, Munger JS, Nunes I, Harpel JG, Mazzieri R, Noguera I & Rifkin DB 1997 TGF-beta latency: biological significance and mechanisms of activation. Stem Cells 15 190197. (https://doi.org/10.1002/stem.150190)

    • Search Google Scholar
    • Export Citation
  • Herrera J, Henke CA & Bitterman PB 2018 Extracellular matrix as a driver of progressive fibrosis. Journal of Clinical Investigation 128 4553. (https://doi.org/10.1172/JCI93557)

    • Search Google Scholar
    • Export Citation
  • Huang G & Brigstock DR 2012 Regulation of hepatic stellate cells by connective tissue growth factor. Frontiers in Bioscience 17 24952507. (https://doi.org/10.2741/4067)

    • Search Google Scholar
    • Export Citation
  • Huang J, Wu S, Barrera J, Matthews K & Pan D 2005 The hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122 421434. (https://doi.org/10.1016/j.cell.2005.06.007)

    • Search Google Scholar
    • Export Citation
  • Hui AY & Friedman SL 2004 Molecular basis of hepatic fibrosis. Expert Reviews in Molecular Medicine 5 410422. (https://doi.org/10.1017/S1462399403005684)

    • Search Google Scholar
    • Export Citation
  • Jia L, Vianna CR, Fukuda M, Berglund ED, Liu C, Tao C, Sun K, Liu T, Harper MJ & Lee CE 2014 Hepatocyte toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nature Communications 12 3878. (https://doi.org/10.1038/ncomms4878)

    • Search Google Scholar
    • Export Citation
  • Khan RS, Bril F, Cusi K & Newsome PN 2019 Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology 70 711724. (https://doi.org/10.1002/hep.30429)

    • Search Google Scholar
    • Export Citation
  • Kim J, Kang W, Kang SH, Park SH, Kim JY, Yang S, Ha SY & Paik Y-H 2020 Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis. Scientific Reports 10 21018. (https://doi.org/10.1038/s41598-020-78056-0)

    • Search Google Scholar
    • Export Citation
  • Kojic S, Radojkovic D & Faulkner G 2011 Muscle ankyrin repeat proteins: their role in striated muscle function in health and disease. Critical Reviews in Clinical Laboratory Sciences 48 269294. (https://doi.org/10.3109/10408363.2011.643857)

    • Search Google Scholar
    • Export Citation
  • Kralj D, Jukić LV, Stojsavljević S, Duvnjak M, Smolić M & Čurčić IB 2016 Hepatitis C virus, insulin resistance, and steatosis. Journal of Clinical and Translational Hepatology 28 6675. (https://doi.org/10.14218/JCTH.2015.00051)

    • Search Google Scholar
    • Export Citation
  • Lau LF 2016 Cell surface receptors for CCN proteins. Journal of Cell Communication and Signaling 10 121127. (https://doi.org/10.1007/s12079-016-0324-z)

    • Search Google Scholar
    • Export Citation
  • Lin Z, Zhou P, von Gise A, Gu F, Ma Q, Chen J, Guo H, van Gorp PRR, Wang DZ & Pu WT 2015 Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circulation Research 116 3545. (https://doi.org/10.1161/CIRCRESAHA.115.304457)

    • Search Google Scholar
    • Export Citation
  • Machado MV & Diehl AM 2014 Liver renewal: detecting misrepair and optimizing regeneration. Mayo Clinic Proceedings 89 120130. (https://doi.org/10.1016/j.mayocp.2013.10.009)

    • Search Google Scholar
    • Export Citation
  • Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H & Diehl AM 2015 Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. Journal of Hepatology 63 962970. (https://doi.org/10.1016/j.jhep.2015.05.031)

    • Search Google Scholar
    • Export Citation
  • Mannaerts I, Leite SB, Verhulst S, Claerhout S, Eysackers N, Thoen LF, Hoorens A, Reynaert H, Halder G & van Grunsven LA 2015 The hippo pathway effector YAP controls mouse hepatic stellate cell activation. Journal of Hepatology 63 679688. (https://doi.org/10.1016/j.jhep.2015.04.011)

    • Search Google Scholar
    • Export Citation
  • Marchesini G, Marzocchi R, Agostini F & Bugianesi E 2005 Nonalcoholic fatty liver disease and the metabolic syndrome. Current Opinion in Lipidology 16 421427. (https://doi.org/10.1097/01.mol.0000174153.53683.f2)

    • Search Google Scholar
    • Export Citation
  • Meindl-Beinker NM & Dooley S 2008 Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis. Journal of Gastroenterology and Hepatology 23 (Supplement 1) S122S127. (https://doi.org/10.1111/j.1440-1746.2007.05297.x)

    • Search Google Scholar
    • Export Citation
  • Moylan CA, Pang H, Dellinger A, Suzuki A, Garrett ME, Guy CD, Murphy SK, Ashley-Koch AE, Choi SS & Michelotti GA et al. 2014 Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology 59 471482. (https://doi.org/10.1002/hep.26661)

    • Search Google Scholar
    • Export Citation
  • Mundi MS, Velapati S, Patel J, Kellogg TA, Abu Dayyeh BK & Hurt RT 2020 Evolution of NAFLD and its management. Nutrition in Clinical Practice 35 7284. (https://doi.org/10.1002/ncp.10449)

    • Search Google Scholar
    • Export Citation
  • Narimatsu M, Samavarchi-Tehrani P, Varelas X & Wrana JL 2015 Distinct polarity cues direct Taz/Yap and TGFβ receptor localization to differentially control TGFβ-induced Smad signaling. Developmental Cell 32 652656. (https://doi.org/10.1016/j.devcel.2015.02.019)

    • Search Google Scholar
    • Export Citation
  • Oh S-H, Swiderska-Syn M, Jewell ML, Premont RT & Diehl AM 2018 Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes. Journal of Hepatology 69 359367. (https://doi.org/10.1016/j.jhep.2018.05.008)

    • Search Google Scholar
    • Export Citation
  • Pan D 2010 The hippo signaling pathway in development and cancer. Developmental Cell 19 491505. (https://doi.org/10.1016/j.devcel.2010.09.011)

    • Search Google Scholar
    • Export Citation
  • Poelstra K 2016 Liver fibrosis in 2015: crucial steps towards an effective treatment. Nature Reviews: Gastroenterology and Hepatology 13 6768. (https://doi.org/10.1038/nrgastro.2015.224)

    • Search Google Scholar
    • Export Citation
  • Rhee EJ 2019 Nonalcoholic fatty liver disease and diabetes: an epidemiological perspective. Endocrinology and Metabolism 34 226233. (https://doi.org/10.3803/EnM.2019.34.3.226)

    • Search Google Scholar
    • Export Citation
  • Satapathy SK & Sanyal AJ 2015 Epidemiology and natural history of nonalcoholic fatty liver disease. Seminars in Liver Disease 35 221235. (https://doi.org/10.1055/s-0035-1562943)

    • Search Google Scholar
    • Export Citation
  • Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J & Brummelkamp TR et al. 2011 Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144 782795. (https://doi.org/10.1016/j.cell.2011.02.031)

    • Search Google Scholar
    • Export Citation
  • Seki E & Brenner DA 2015 Recent advancement of molecular mechanisms of liver fibrosis. Journal of Hepato Biliary: Pancreatic Sciences 22 512518. (https://doi.org/10.1002/jhbp.245)

    • Search Google Scholar
    • Export Citation
  • Tumaneng K, Guan K-L, Russell RC, Yimlamai D, Basnet H, Mahadevan N, Fitamant J, Bardeesy N, Camargo FD & Guan KL 2012 YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29. Nature Cell Biology 14 13221329. (https://doi.org/10.1038/ncb2615)

    • Search Google Scholar
    • Export Citation
  • Wang K, Degerny C, Xu M & Yang XJ 2009 YAP, TAZ, and Yorkie: a conserved family of signal-responsive transcriptional coregulators in animal development and human disease. Biochemistry and Cell Biology 87 7791. (https://doi.org/10.1139/O08-114)

    • Search Google Scholar
    • Export Citation
  • Wang W, Xiao ZD, Li X, Aziz KE, Gan B, Johnson RL & Chen J 2015 AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nature Cell Biology 17 490499. (https://doi.org/10.1038/ncb3113)

    • Search Google Scholar
    • Export Citation
  • Weiskirchen R & Tacke F 2016 Liver fibrosis: from pathogenesis to novel therapies. Digestive Diseases 34 410422. (https://doi.org/10.1159/000444556)

    • Search Google Scholar
    • Export Citation
  • Yadav H, Devalaraja S, Chung ST & Rane SG 2017 TGF-β1/Smad3 pathway targets PP2A-AMPK-FoxO1 signaling to regulate hepatic gluconeogenesis. Journal of Biological Chemistry 292 34203432. (https://doi.org/10.1074/jbc.M116.764910)

    • Search Google Scholar
    • Export Citation
  • Yao T, Deng Z, Gao Y, Sun J, Kong X, Huang Y, He Z, Xu Y, Chang Y & Yu KJ 2017 Ire1α in pomc neurons is required for thermogenesis and glycemia. Diabetes 66 663673. (https://doi.org/10.2337/db16-0533)

    • Search Google Scholar
    • Export Citation
  • Ye X, Deng Y & Lai ZC 2012 Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila. Developmental Biology 369 115123. (https://doi.org/10.1016/j.ydbio.2012.06.014)

    • Search Google Scholar
    • Export Citation
  • Yu H-X, Yao Y, Bu F-T, Chen Y, Wu Y-T, Yang Y, Chen X, Zhu Y, Wang Q & Pan X-Y 2019 Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells. Molecular Immunology 107 2940. (https://doi.org/10.1016/j.molimm.2019.01.004)

    • Search Google Scholar
    • Export Citation
  • Zhang K, Li L, Qi Y, Zhu X, Gan B, DePinho RA, Averitt T & Guo S 2012 Hepatic suppression of FoxO1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice. Endocrinology 153 631646. (https://doi.org/10.1210/en.2011-1527)

    • Search Google Scholar
    • Export Citation
  • Zhang D, Zhang R, Guo Z, Gao M, Huang L, You L, Zhang P, Li J, Su X & Wu H et al. 2018 Desmin- and vimentin-mediated hepatic stellate cell-targeting radiotracer 99mTc-GlcNAc-PEI for liver fibrosis imaging with SPECT. Theranostics 8 13401349. (https://doi.org/10.7150/thno.22806)

    • Search Google Scholar
    • Export Citation
  • Zhang K, Guo X, Yan H, Wu Y, Pan Q, Shen JZ, Li X, Chen Y, Li L & Qi Y 2019 Phosphorylation of forkhead protein FoxO1 at S253 regulates glucose homeostasis in mice. Endocrinology 160 13331347. (https://doi.org/10.1210/en.2018-00853)

    • Search Google Scholar
    • Export Citation