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Cited by 99Liver physiology and pathologyLiver Disease and TransplantationOrgan Transplantation Techniques and Outcomes

Loss of liver function in chronic liver disease: An identity crisis

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Berasain, Carmen, Arechederra, Maria, Argemí, Josepmaria, Fernández-Barrena, Maite G., Avila, Matías A.·2023·Journal of Hepatology
DOI 10.1016/j.jhep.2022.09.001
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Abstract

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.

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  • Breakdown in liver functions in advanced stages of liver injuries and in cancer results from hepatocyte loss of identity stemming from compromised expression of the hepatic core transcriptional regulatory circuitry transcription factors.

    “breakdown in liver functions in advanced stages of liver injuries and in cancer results from hepatocyte loss of identity stemming from compromised expression of the hepatic CoRC TFs (Dubois et al, 2020a; Berasain et al, 2022).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Berasain et al, 2022

    The Key points and Conclusions link loss of liver function during chronic injury to impaired core liver transcription factors and loss of hepatocyte identity. The ‘Loss of hepatic function in liver disease’ section says persistent impairment creates conditions favourable to hepatocellular carcinoma, but does not establish that this mechanism causes liver-function breakdown in cancer itself. The indexed passages do not provide individual page numbers. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Hepatocyte partial loss of identity is a hallmark of diseased livers.

    “we and others have reported that hepatocyte partial loss of identity is a hallmark of diseased livers [recently reviewed in (Berasain et al, 2022)].”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Berasain et al, 2022

  • Loss of hepatocyte identity is a main feature of tumorigenesis and has broader pathophysiological relevance including loss of activity of severely injured livers.

    “Loss of hepatocyte identity is a main feature of tumorigenesis, but is now ascribed a broader pathophysiological relevance including loss of activity of severely injured livers (Berasain et al, 2022).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Berasain et al, 2022

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  1. Huppert SS, Iwafuchi-Doi M. Molecular regulation of mammalian hepatic ar- chitecture. Curr Top Dev Biol 2019;132:91-136. https://doi.org/10.1016/BS. CTDB.2018.12.003. · DOI
  2. Ben-Moshe S, Itzkovitz S. Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol 2019;16:395-410. https://doi.org/10.1038/ S41575-019-0134-X. · DOI · Paper page
  3. Almeida JI, Tenreiro MF, Martinez-Santamaria L, Guerrero-Aspizua S, Gisbert JP, Alves PM, et al. Hallmarks of the human intestinal microbiome on liver maturation and function. J Hepatol 2022;76:694-725. https://doi.org/10. 1016/J.JHEP.2021.10.015. · DOI
  4. Paris J, Henderson NC. Liver zonation, revisited. Hepatology 2022. https:// doi.org/10.1002/HEP.32408. · DOI
  5. Tachmatzidi EC, Galanopoulou O, Talianidis I. Transcription control of liver development. Cells 2021;10. https://doi.org/10.3390/CELLS10082026. · DOI · Paper page
  6. Halpern KB, Shenhav R, Matcovitch-Natan O, Tóth B, Lemze D, Golan M, et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 2017;542:352-356. https://doi.org/10. 1038/NATURE21065. · DOI · Paper page
  7. Macchi F, Sadler KC. Unraveling the epigenetic basis of liver development, regeneration and disease. Trends Genet 2020. https://doi.org/10.1016/j.tig. 2020.05.002. · DOI
  8. Recalde M, Gárate-Rascón M, Herranz JM, Elizalde M, Azkona M, Unfried JP, et al. DNA methylation regulates a set of long non-coding RNAs compromising hepatic identity during hepatocarcinogenesis. Cancers (Basel) 2022;14. https://doi.org/10.3390/CANCERS14092048. · DOI · Paper page
  9. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019;70:151-171. https://doi.org/10.1016/J.JHEP. 2018.09.014. · DOI · Paper page
  10. Sharma P, Arora A. Clinical presentation of alcoholic liver disease and non- alcoholic fatty liver disease: spectrum and diagnosis. Transl Gastroenterol Hepatol 2020;5. https://doi.org/10.21037/TGH.2019.10.02. · DOI
  11. Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet (London, England) 2021;398:1359-1376. https://doi.org/10. 1016/S0140-6736(21)01374-X. · DOI · Paper page
  12. Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021;75(Suppl 1):S49-S66. https://doi.org/10.1016/J.JHEP.2021.01.002. · DOI
  13. Thomes PG, Rasineni K, Saraswathi V, Kharbanda KK, Clemens DL, Sweeney SA, et al. Natural recovery by the liver and other organs after chronic alcohol use. Alcohol Res 2021;41. https://doi.org/10.35946/ARCR. V41.1.05. · DOI
  14. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a trans- lational success story. Gut 2015;64:830-841. https://doi.org/10.1136/gutjnl- 2014-306842. · DOI
  15. Jalan R, D'Amico G, Trebicka J, Moreau R, Angeli P, Arroyo V. New clinical and pathophysiological perspectives defining the trajectory of cirrhosis. J Hepatol 2021;75(Suppl 1):S14-S26. https://doi.org/10.1016/J.JHEP.2021. 01.018. · DOI
  16. Yanaga K, Honda H, Ikeda Y, Nishizaki AT, Yamamoto K, Sugimachi K, et al. Significance of liver size in hepatic surgery. HPB Surg 1997;10:195-200. https://doi.org/10.1155/1997/34842. · DOI
  17. Berasain C, Avila MA. Regulation of hepatocyte identity and quiescence. Cell Mol Life Sci 2015;72:3831-3851. https://doi.org/10.1007/s00018-015-1970-7. · DOI
  18. Haep N, Florentino RM, Squires JE, Bell A, Soto-Gutierrez A. The inside-out of end-stage liver disease: hepatocytes are the keystone. Semin Liver Dis 2021;41:213-224. https://doi.org/10.1055/S-0041-1725023. · DOI
  19. Nishina H. Physiological and pathological roles of the Hippo-YAP/TAZ signaling pathway in liver formation, homeostasis, and tumorigenesis. Cancer Sci 2022. https://doi.org/10.1111/CAS.15352. · DOI
  20. Russell JO, Camargo FD. Hippo signalling in the liver: role in development, regeneration and disease. Nat Rev Gastroenterol Hepatol 2022;19. https:// doi.org/10.1038/S41575-021-00571-W. · DOI
  21. Mayran A, Drouin J. Pioneer transcription factors shape the epigenetic landscape. J Biol Chem 2018;293:13795-13804. https://doi.org/10.1074/ JBC.R117.001232. · DOI
  22. Lau HH, Ng NHJ, Loo LSW, Jasmen JB, Teo AKK. The molecular functions of hepatocyte nuclear factors -in and beyond the liver. J Hepatol 2018;68:1033-1048. https://doi.org/10.1016/J.JHEP.2017.11.026. · DOI · Paper page
  23. Kropp PA, Gannon M. Onecut transcription factors in development and disease. Trends Dev Biol 2016;9:43-57.
  24. Clotman F, Lemaigre FP. Control of hepatic differentiation by activin/ TGFbeta signaling. Cell Cycle 2006;5:168-171. https://doi.org/10.4161/CC. 5.2.2341. · DOI
  25. Sladek FM, Zhong W, Lai E, Darnell JE. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 1990;4:2353-2365. https://doi.org/10.1101/GAD.4.12B.2353. · DOI · Paper page
  26. Dubois V, Staels B, Lefebvre P, Verzi MP, Eeckhoute J. Control of cell identity by the nuclear receptor HNF4 in organ pathophysiology. Cells 2020;9. https://doi.org/10.3390/CELLS9102185. · DOI · Paper page
  27. Dean S, Tang JI, Seckl JR, Nyirenda MJ. Developmental and tissue-specific regulation of hepatocyte nuclear factor 4-alpha (HNF4-alpha) isoforms in rodents. Gene Expr 2010;14:337-344. https://doi.org/10.3727/ 105221610X12717040569901. · DOI
  28. Lu H. Crosstalk of HNF4 a with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. Acta Pharm Sin B 2016;6:393-408. https://doi.org/10.1016/J.APSB.2016.07.003. · DOI
  29. Li J, Ning G, Duncan SA. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 2000;14:464-474. https://doi. org/10.1101/gad.14.4.464. · DOI
  30. Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003;34:292-296. https:// doi.org/10.1038/NG1175. · DOI · Paper page
  31. Westmacott A, Burke ZD, Oliver G, Slack JMW, Tosh D. C/EBPalpha and C/EBPbeta are markers of early liver development. Int J Dev Biol 2006;50:653-657. https://doi.org/10.1387/IJDB.062146AW. · DOI
  32. Lemaigre FP. Development of the intrahepatic and extrahepatic biliary tract: a framework for understanding congenital diseases. Annu Rev Pathol 2020;15:1- 22. https://doi.org/10.1146/ANNUREV-PATHMECHDIS-012418-013013. · DOI
  33. Hatzis P, Talianidis I. Regulatory mechanisms controlling human hepatocyte nuclear factor 4alpha gene expression. Mol Cell Biol 2001;21:7320-7330. https://doi.org/10.1128/MCB.21.21.7320-7330.2001. · DOI
  34. Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Cereghini S. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 1999;126:4795-4805. https://doi.org/10.1242/DEV.126. 21.4795. · DOI
  35. Kyrmizi I, Hatzis P, Katrakili N, Tronche F, Gonzalez FJ, Talianidis I. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 2006;20:2293-2305. https://doi.org/10.1101/ GAD.390906. · DOI · Paper page
  36. Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell 2010;18:175-189. https://doi.org/10.1016/J.DEVCEL. 2010.01.011. · DOI · Paper page
  37. Briançon N, Bailly A, Clotman F, Jacquemin P, Lemaigre FP, Weiss MC. Expression of the alpha7 isoform of hepatocyte nuclear factor (HNF) 4 is activated by HNF6/OC-2 and HNF1 and repressed by HNF4alpha1 in the liver. J Biol Chem 2004;279:33398-33408. https://doi.org/10.1074/ JBC.M405312200. · DOI
  38. Xu C-R, Zaret KS. Chromatin "pre-pattern" and epigenetic modulation in the cell fate choice of liver over pancreas in the endoderm. Nucleus 2012;3:150- 154. https://doi.org/10.4161/NUCL.19321. · DOI
  39. Elsherbiny A, Dobreva G. Epigenetic memory of cell fate commitment. Curr Opin Cell Biol 2021;69:80-87. https://doi.org/10.1016/J.CEB.2020.12.014. · DOI
  40. Karagianni P, Moulos P, Schmidt D, Odom DT, Talianidis I. Bookmarking by non-pioneer transcription factors during liver development establishes competence for future gene activation. Cell Rep 2020;30:1319-1328.e6. https://doi.org/10.1016/J.CELREP.2020.01.006. · DOI
  41. Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and re- sults in endoplasmic reticulum stress. Nat Med 2008;14:828-836. https:// doi.org/10.1038/NM.1853. · DOI
  42. Feng R, Kan K, Sticht C, Li Y, Wang S, Liu H, et al. A hierarchical regulatory network ensures stable albumin transcription under various pathophysio- logical conditions. Hepatology 2022. https://doi.org/10.1002/HEP.32414. · DOI
  43. Ballester B, Medina-Rivera A, Schmidt D, Gonzàlez-Porta M, Carlucci M, Chen X, et al. Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways. Elife 2014;3:1-29. https://doi.org/10.7554/ELIFE.02626. · DOI · Paper page
  44. Dubois-Chevalier J, Dubois V, Dehondt H, Mazrooei P, Mazuy C, Sérandour AA, et al. The logic of transcriptional regulator recruitment ar- chitecture at cis-regulatory modules controlling liver functions. Genome Res 2017;27:985-996. https://doi.org/10.1101/GR.217075.116. · DOI · Paper page
  45. Dubois-Chevalier J, Dubois V, Staels B, Lefebvre P, Eeckhoute J. Per- spectives on the use of super-enhancers as a defining feature of cell/tissue- identity genes. Epigenomics 2020;12:715-723. https://doi.org/10.2217/EPI- 2019-0290. · DOI
  46. Gérard C, Tys J, Lemaigre FP. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin Cell Dev Biol 2017;66:43- 50. https://doi.org/10.1016/J.SEMCDB.2016.12.003. · DOI
  47. Joo MS, Koo JH, Kim TH, Kim YS, Kim SG. LRH1-driven transcription factor circuitry for hepatocyte identity: super-enhancer cistromic analysis. EBio- Medicine 2019;40:488-503. https://doi.org/10.1016/J.EBIOM.2018.12.056. · DOI
  48. Hayhurst GP, Lee Y-H, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001;21:1393- 1403. https://doi.org/10.1128/MCB.21.4.1393-1403.2001. · DOI · Paper page
  49. Martinez-Jimenez CP, Kyrmizi I, Cardot P, Gonzalez FJ, Talianidis I. Hepa- tocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol 2010;30:565-577. https://doi.org/10.1128/MCB.00927-09. · DOI
  50. Santangelo L, Marchetti A, Cicchini C, Conigliaro A, Conti B, Mancone C, et al. The stable repression of mesenchymal program is required for hepa- tocyte identity: a novel role for hepatocyte nuclear factor 4a. Hepatology 2011;53:2063-2074. https://doi.org/10.1002/HEP.24280. · DOI
  51. Wu H, Reizel T, Wang YJ, Lapiro JL, Kren BT, Schug J, et al. A negative reciprocal regulatory axis between cyclin D1 and HNF4a modulates cell cycle progression and metabolism in the liver. Proc Natl Acad Sci U S A 2020;117:17177-17186. https://doi.org/10.1073/PNAS.2002898117. · DOI
  52. Odom DT, Zizlsperger H, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 2004;303:1378-1381. https://doi.org/10.1126/SCIENCE.1089769. · DOI
  53. Palierne G, Fabre A, Solinhac R, Le Péron C, Avner S, Lenfant F, et al. Changes in gene expression and estrogen receptor cistrome in mouse liver upon acute E2 treatment. Mol Endocrinol 2016;30:709-732. https://doi.org/ 10.1210/ME.2015-1311. · DOI
  54. Alvarez-Sola G, Uriarte I, Latasa MU, Urtasun R, Bárcena-Varela M, Elizalde M, et al. Fibroblast growth factor 15/19 in hepatocarcinogenesis. Dig Dis 2017;35:158-165. https://doi.org/10.1159/000450905. · DOI
  55. Dubois V, Gheeraert C, Vankrunkelsven W, Dubois-Chevalier J, Dehondt H, Bobowski-Gerard M, et al. Endoplasmic reticulum stress actively sup- presses hepatic molecular identity in damaged liver. Mol Syst Biol 2020;16. https://doi.org/10.15252/MSB.20199156. · DOI · Paper page
  56. Huck I, Gunewardena S, Espanol-Suner R, Willenbring H, Apte U. Hepato- cyte nuclear factor 4 alpha activation is essential for termination of liver regeneration in mice. Hepatology 2019;70:666-681. https://doi.org/10.1002/ HEP.30405. · DOI
  57. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, et al. An HNF4a-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011;147:1233-1247. https://doi.org/10. 1016/J.CELL.2011.10.043. · DOI
  58. Ning BF, Ding J, Liu J, Yin C, Xu WP, Cong WM, et al. Hepatocyte nuclear factor 4a-nuclear factor-jB feedback circuit modulates liver cancer progres- sion. Hepatology 2014;60:1607-1619. https://doi.org/10.1002/HEP.27177. · DOI
  59. Morimoto A, Kannari M, Tsuchida Y, Sasaki S, Saito C, Matsuta T, et al. An HNF4a-microRNA-194/192 signaling axis maintains hepatic cell function. J Biol Chem 2017;292:10574-10585. https://doi.org/10.1074/JBC. M117.785592. · DOI
  60. Hu S, Molina L, Tao J, Liu S, Hassan M, Singh S, et al. NOTCH-YAP1/TEAD- DNMT1 Axis drives hepatocyte reprogramming into intrahepatic chol- angiocarcinoma. Gastroenterology 2022;163. https://doi.org/10.1053/J. GASTRO.2022.05.007. · DOI
  61. Navi LR Ben, Tsukerman A, Feldman A, Melamed P, Tomic M, Stojilkovic SS, et al. Alternative RNA splicing in the pathogenesis of liver disease. Front Endocrinol (Lausanne) 2017;8. https://doi.org/10.3389/FENDO.2017.00133. · DOI
  62. Berasain C, Goñi S, Castillo J, Latasa MU, Prieto J, Ávila MA. Impairment of pre-mRNA splicing in liver disease: mechanisms and consequences. World J Gastroenterol 2010;16:3091-3102. https://doi.org/10.3748/WJG.V16. I25.3091. · DOI
  63. Bhate A, Parker DJ, Bebee TW, Ahn J, Arif W, Rashan EH, et al. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat Commun 2015;6. https://doi.org/10.1038/NCOMMS 9768. · DOI · Paper page
  64. Cheng Y, Luo C, Wu W, Xie Z, Fu X, Feng Y. Liver-specific deletion of SRSF2 caused acute liver failure and early death in mice. Mol Cell Biol 2016;36:1628-1638. https://doi.org/10.1128/MCB.01071-15. · DOI
  65. Sen S, Jumaa H, Webster NJG. Splicing factor SRSF3 is crucial for hepa- tocyte differentiation and metabolic function. Nat Commun 2013;4. https:// doi.org/10.1038/NCOMMS2342. · DOI
  66. Elizalde M, Urtasun R, Azkona M, Latasa MU, Goñi S, García-Irigoyen O, et al. Splicing regulator SLU7 is essential for maintaining liver homeostasis. J Clin Invest 2014;124:2909-2920. https://doi.org/10.1172/JCI74382. · DOI
  67. Jiménez M, Urtasun R, Elizalde M, Azkona M, Latasa MU, Uriarte I, et al. Splicing events in the control of genome integrity: role of SLU7 and trun- cated SRSF3 proteins. Nucleic Acids Res 2019;47:3450-3466. https://doi. org/10.1093/nar/gkz014. · DOI
  68. Haj M, Rockey DC. Predictors of clinical outcomes in cirrhosis patients. Curr Opin Gastroenterol 2018;34:266-271. https://doi.org/10.1097/MOG.0000 000000000450. · DOI
  69. Lemmer P, Pospiech JC, Canbay A. Liver failure-future challenges and remaining questions. Ann Transl Med 2021;9. https://doi.org/10.21037/ ATM-20-4968. 734-734. · DOI
  70. Lin T, Feng R, Liebe R, Weng HL. Liver progenitor cells in massive hepatic necrosis-how can a patient survive acute liver failure? Biomolecules 2022;12. https://doi.org/10.3390/BIOM12010066. · DOI
  71. Rutkowski DT. Liver function and dysfunction -a unique window into the physiological reach of ER stress and the unfolded protein response. FEBS J 2019;286:356-378. https://doi.org/10.1111/FEBS.14389. · DOI
  72. Han H, Desert R, Das S, Song Z, Athavale D, Ge X, et al. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020;73:933-951. https://doi.org/10.1016/J.JHEP.2020.04.033. · DOI · Paper page
  73. Avila MA, Berasain C, Torres L, Martín-Duce A, Corrales FJ, Yang H, et al. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 2000;33:907-914. https://doi.org/10.1016/S0168-8278(00)80122-1. · DOI
  74. Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 2012;92:1515-1542. https://doi.org/10.1152/PHYSREV. 00047.2011. · DOI
  75. Torres L, Ávila MatA, Carretero MV, Latasa MU, Caballería J, López- Rodas G, et al. Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation. FASEB J 2000;14:95-102. https://doi.org/10.1096/fasebj.14.1.95. · DOI
  76. Mirpuri E, García-Trevijano ER, Castilla-Cortazar I, Berasain C, Quiroga J, Rodriguez-Ortigosa C, et al. Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I. Int J Biochem Cell Biol 2002;34:242-252. https://doi.org/10.1016/S1357-2725(01)00123-6. · DOI
  77. Liu L, Yannam GR, Nishikawa T, Yamamoto T, Basma H, Ito R, et al. The microenvironment in hepatocyte regeneration and function in rats with advanced cirrhosis. Hepatology 2012;55:1529-1539. https://doi.org/10. 1002/HEP.24815. · DOI
  78. Guzman-Lepe J, Cervantes-Alvarez E, Collin de l'Hortet A, Wang Y, Mars WM, Oda Y, et al. Liver-enriched transcription factor expression relates to chronic hepatic failure in humans. Hepatol Commun 2018;2:582-594. https://doi.org/10.1002/HEP4.1172. · DOI
  79. Argemi J, Latasa MU, Atkinson SR, Blokhin IO, Massey V, Gue JP, et al. Defective HNF4alpha-dependent gene expression as a driver of hepato- cellular failure in alcoholic hepatitis. Nat Commun 2019;10. https://doi.org/ 10.1038/S41467-019-11004-3. · DOI
  80. Guldiken N, Argemi J, Gurbuz B, Atkinson SR, Oliverius M, Fila P, et al. Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha ac- tivity and hepatocyte function in liver diseases. BMC Med 2021;19. https:// doi.org/10.1186/S12916-021-01917-6. · DOI
  81. Bou Saleh M, Louvet A, Ntandja-Wandji LC, Boleslawski E, Gnemmi V, Lassailly G, et al. Loss of hepatocyte identity following aberrant YAP acti- vation: a key mechanism in alcoholic hepatitis. J Hepatol 2021;75:912-923. https://doi.org/10.1016/J.JHEP.2021.05.041. · DOI · Paper page
  82. Berasain C, Herrero JI, García-Trevijano ER, Avila MA, Esteban JI, Mato JM, et al. Expression of Wilms' tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Hep- atology 2003;38:148-157. https://doi.org/10.1053/JHEP.2003.50269. · DOI
  83. Hyun J, Oh SH, Premont RT, Guy CD, Berg CL, Diehl AM. Dysregulated activation of fetal liver programme in acute liver failure. Gut 2019;68:1076- 1087. https://doi.org/10.1136/GUTJNL-2018-317603. · DOI
  84. Kim A, Wu X, Allende DS, Nagy LE. Gene deconvolution reveals aberrant liver regeneration and immune cell infiltration in alcohol-associated hepatitis. Hepatology 2021;74:987-1002. https://doi.org/10.1002/HEP.31759. · DOI
  85. He Z, Peng C, Li T, Li J. Cell differentiation trajectory in liver cirrhosis pre- dicts hepatocellular carcinoma prognosis and reveals potential biomarkers for progression of liver cirrhosis to hepatocellular carcinoma. Front Genet 2022;13. https://doi.org/10.3389/FGENE.2022.858905. · DOI
  86. Galle PR, Foerster F, Kudo M, Chan SL, Llovet JM, Qin S, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int 2019;39:2214-2229. https://doi.org/10.1111/LIV.14223. · DOI · Paper page
  87. Wang W, Yao LJ, Shen W, Ding K, Shi PM, Chen F, et al. FOXA2 alleviates CCl 4-induced liver fibrosis by protecting hepatocytes in mice. Sci Rep 2017;7. https://doi.org/10.1038/S41598-017-15831-6. · DOI
  88. McDaniel K, Meng F, Wu N, Sato K, Venter J, Bernuzzi F, et al. Forkhead box A2 regulates biliary heterogeneity and senescence during cholestatic liver injury in mice. Hepatology 2017;65:544-559. https://doi.org/10.1002/ HEP.28831. · DOI
  89. Wang S, Feng R, Wang SS, Liu H, Shao C, Li Y, et al. FOXA2 prevents hyperbilirubinaemia in acute liver failure by maintaining apical MRP2 expression. Gut 2022. https://doi.org/10.1136/GUTJNL-2022-326987. gutjnl-2022-326987. · DOI
  90. Moya M, Benet M, Guzmán C, Tolosa L, García-Monzón C, Pareja E, et al. Foxa1 reduces lipid accumulation in human hepatocytes and is down- regulated in nonalcoholic fatty liver. PLoS One 2012;7. https://doi.org/10. 1371/JOURNAL.PONE.0030014. · DOI
  91. Dong R, Yang Y, Shen Z, Zheng C, Jin Z, Huang Y, et al. Forkhead box A3 attenuated the progression of fibrosis in a rat model of biliary atresia. Cell Death Dis 2017;8. https://doi.org/10.1038/CDDIS.2017.99. · DOI
  92. Lazarevich NL, Cheremnova OA, Varga EV, Ovchinnikov DA, Kudrjavtseva EI, Morozova OV, et al. Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors. Hepatology 2004;39:1038-1047. https://doi.org/10.1002/ HEP.20155. · DOI
  93. Hellerbrand C, Amann T, Schlegel J, Wild P, Bataille F, Spruss T, et al. The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma. Gut 2008;57:243-251. https://doi.org/10.1136/GUT.2007.129544. · DOI
  94. Zeng X, Lin Y, Yin C, Zhang X, Ning BF, Zhang Q, et al. Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 2011;54:2036-2047. https://doi.org/10.1002/HEP.24647. · DOI
  95. Teeli AS, Łuczy nska K, Haque E, Gayas MA, Winiarczyk D, Taniguchi H. Disruption of tumor suppressors HNF4a/HNF1a causes tumorigenesis in liver. Cancers (Basel) 2021;13. https://doi.org/10.3390/CANCERS1321 5357. · DOI
  96. Perugorria MJ, Castillo J, Latasa MU, Goñi S, Segura V, Sangro B, et al. Wilms' tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res 2009;69:1358-1367. https://doi.org/10.1158/0008-5472.CAN-08-2545. · DOI
  97. Xu Y, Zalzala M, Xu J, Li Y, Yin L, Zhang Y. A metabolic stress-inducible miR-34a-HNF4a pathway regulates lipid and lipoprotein metabolism. Nat Commun 2015;6. https://doi.org/10.1038/NCOMMS8466. · DOI
  98. Xu J, Xu Y, Li Y, Jadhav K, You M, Yin L, et al. Carboxylesterase 1 is regulated by hepatocyte nuclear factor 4a and protects against alcohol- and MCD diet-induced liver injury. Sci Rep 2016;6. https://doi.org/10. 1038/SREP24277. · DOI
  99. Sahoo S, Singh D, Chakraborty P, Jolly MK. Emergent properties of the HNF4a-PPARc network may drive consequent phenotypic plasticity in NAFLD. J Clin Med 2020;9. https://doi.org/10.3390/JCM9030870. · DOI
  100. Lin T, Wang S, Munker S, Jung K, Macías-Rodríguez RU, Ruiz- Margáin A, et al. Follistatin-controlled activin-HNF4a-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure. Hepatology 2022;75:322-337. https://doi.org/10.1002/HEP.32119. · DOI
  101. Gárate-Rascón M, Recalde M, Jimenez M, Elizalde M, Azkona M, Uriarte I, et al. Splicing factor SLU7 prevents oxidative stress-mediated hepatocyte nuclear factor 4a degradation, preserving hepatic differentiation and pro- tecting from liver damage. Hepatology 2021;74:2791-2807. https://doi.org/ 10.1002/HEP.32029. · DOI
  102. Yeh MM, Bosch DE, Daoud SS. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases. World J Gastroenterol 2019;25:4074- 4091. https://doi.org/10.3748/WJG.V25.I30.4074. · DOI
  103. Tanaka T, Jiang S, Hotta H, Takano K, Iwanari H, Sumi K, et al. Dysregu- lated expression of P1 and P2 promoter-driven hepatocyte nuclear factor- 4alpha in the pathogenesis of human cancer. J Pathol 2006;208:662-672. https://doi.org/10.1002/PATH.1928. · DOI
  104. Nakhei H, Lingott A, Lemm I, Ryffel GU. An alternative splice variant of the tissue specific transcription factor HNF4alpha predominates in undiffer- entiated murine cell types. Nucleic Acids Res 1998;26:497-504. https://doi. org/10.1093/NAR/26.2.497. · DOI
  105. Torres-Padilla ME, Fougère-Deschatrette C, Weiss MC. Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3' end splicing. Mech Dev 2001;109:183- 193. https://doi.org/10.1016/S0925-4773(01)00521-4. · DOI · Paper page
  106. Briançon N, Weiss MC. In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping. EMBO J 2006;25:1253-1262. https:// doi.org/10.1038/SJ.EMBOJ.7601021. · DOI
  107. Hatzis P, Kyrmizi I, Talianidis I. Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nu- clear factor 4alpha expression. Mol Cell Biol 2006;26:7017-7029. https:// doi.org/10.1128/MCB.00297-06. · DOI
  108. Xu Q, Li Y, Gao X, Kang K, Williams JG, Tong L, et al. HNF4a regulates sulfur amino acid metabolism and confers sensitivity to methionine re- striction in liver cancer. Nat Commun 2020;11. https://doi.org/10.1038/ S41467-020-17818-W. · DOI
  109. Florentino RM, Fraunhoffer NA, Morita K, Takeishi K, Ostrowska A, Achreja A, et al. Cellular location of HNF4a is linked with terminal liver failure in humans. Hepatol Commun 2020;4:859-875. https://doi.org/10. 1002/HEP4.1505. · DOI
  110. Yu D, Chen G, Pan M, Zhang J, He W, Liu Y, et al. High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4a and leads to hepatic steatosis in mice. J Cell Physiol 2018;233:4770-4782. https://doi.org/10. 1002/JCP.26270. · DOI
  111. Noce V, Battistelli C, Cozzolino AM, Consalvi V, Cicchini C, Strippoli R, et al. YAP integrates the regulatory Snail/HNF4a circuitry controlling epithelial/hepatocyte differentiation. Cell Death Dis 2019;10. https://doi. org/10.1038/S41419-019-2000-8. · DOI
  112. Desai SS, Tung JC, Zhou VX, Grenert JP, Malato Y, Rezvani M, et al. Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha. Hepatology 2016;64:261-275. https://doi.org/10.1002/HEP.28450. · DOI · Paper page
  113. Filliol A, Schwabe RF. Contributions of fibroblasts, extracellular matrix, stiffness, and mechanosensing to hepatocarcinogenesis. Semin Liver Dis 2019;39:315-333. https://doi.org/10.1055/S-0039-1685539. · DOI
  114. Gibert-ramos A, Sanfeliu-redondo D, Aristu-zabalza P, Martínez-alcocer A, Gracia-sancho J, Guixé-muntet S, et al. The hepatic sinusoid in chronic liver disease: the optimal milieu for cancer. Cancers (Basel) 2021;13. https://doi.org/10.3390/CANCERS13225719. · DOI
  115. Pinto C, Giordano DM, Maroni L, Marzioni M. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim Biophys Acta Mol Basis Dis 2018;1864:1270-1278. https://doi.org/10. 1016/J.BBADIS.2017.07.024. · DOI
  116. Molina L, Nejak-Bowen K, Monga SP. Role of YAP1 signaling in biliary development, repair, and disease. Semin Liver Dis 2022;42:17-33. https:// doi.org/10.1055/S-0041-1742277. · DOI
  117. Wang AW, Wang YJ, Zahm AM, Morgan AR, Wangensteen KJ, Kaestner KH. The dynamic chromatin architecture of the regenerating liver. Cell Mol Gastroenterol Hepatol 2020;9:121-143. https://doi.org/10.1016/J. JCMGH.2019.09.006. · DOI
  118. Arechederra M, Berasain C, Avila MA, Fernández-Barrena MG. Chromatin dynamics during liver regeneration. Semin Cell Dev Biol 2020;97:38-46. https://doi.org/10.1016/j.semcdb.2019.03.004. · DOI · Paper page
  119. Porukala M, Vinod PK. Systems-level analysis of transcriptome reorga- nization during liver regeneration. Mol Omi 2022;18:315-327. https://doi. org/10.1039/D1MO00382H. · DOI
  120. Alvarez-Sola G, Uriarte I, Latasa MU, Jimenez M, Barcena-Varela M, Santamaría E, et al. Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice. Cell Death Dis 2017;8:e3083. https://doi.org/10.1038/cddis. 2017.480. · DOI
  121. Argemí J, Kress TR, Chang HCY, Ferrero R, Bértolo C, Moreno H, et al. X- Box binding protein 1 regulates unfolded protein, acute-phase, and DNA damage responses during regeneration of mouse liver. Gastroenterology 2017;152:1203-1216.e15. https://doi.org/10.1053/J.GASTRO.2016. 12.040. · DOI
  122. Gazelakis K, Majeed A, Kemp W, Di Muzio B, Gerstenmaier J, Cheung W, et al. Liver disease severity predicts carcinogenesis of dysplastic liver nodules in cirrhosis. Sci Rep 2021;11. https://doi.org/10.1038/S41598- 021-00474-5. · DOI
  123. Chen P, Luo Q, Huang C, Gao Q, Li L, Chen J, et al. Pathogenesis of non- alcoholic fatty liver disease mediated by YAP. Hepatol Int 2018;12:26-36. https://doi.org/10.1007/S12072-017-9841-Y. · DOI
  124. Mooring M, Fowl BH, Lum SZC, Liu Y, Yao K, Softic S, et al. Hepatocyte stress increases expression of yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology 2020;71:1813-1830. https://doi.org/ 10.1002/HEP.30928. · DOI · Paper page
  125. Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, et al. Hepa- tocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab 2016;24:848-862. https://doi.org/10.1016/J. CMET.2016.09.016. · DOI · Paper page
  126. Wang X, Zeldin S, Shi H, Zhu C, Saito Y, Corey KE, et al. TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis. J Hepatol 2022;76:910-920. https://doi.org/10.1016/J.JHEP.2021.11.031. · DOI
  127. Hyun J, Al Abo M, Dutta RK, Oh SH, Xiang K, Zhou X, et al. Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease. J Hepatol 2021;75:623-633. https://doi. org/10.1016/J.JHEP.2021.04.033. · DOI
  128. Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L, Angioni MM, et al. YAP activation is an early event and a potential thera- peutic target in liver cancer development. J Hepatol 2014;61:1088-1096. https://doi.org/10.1016/J.JHEP.2014.06.033. · DOI
  129. Fitamant J, Kottakis F, Benhamouche S, Tian HS, Chuvin N, Parachoniak CA, et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep 2015;10:1692-1707. https://doi.org/10.1016/J.CELREP.2015.02.027. · DOI · Paper page
  130. Liu Y, Zhuo S, Zhou Y, Ma L, Sun Z, Wu X, et al. Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcino- genesis. J Hepatol 2022;76:652-664. https://doi.org/10.1016/J.JHEP. 2021.11.010. · DOI
  131. Cai WY, Lin LY, Hao H, Zhang SM, Ma F, Hong XX, et al. Yes-associated protein/TEA domain family member and hepatocyte nuclear factor 4-alpha (HNF4a) repress reciprocally to regulate hepatocarcinogenesis in rats and mice. Hepatology 2017;65:1206-1221. https://doi.org/10.1002/HEP.28911. · DOI
  132. Wu B-K, Mei S-C, Chen EH, Zheng Y, Pan D. YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis. Nat Genet 2022. https://doi.org/10.1038/ S41588-022-01119-7. · DOI
  133. Yang T, Poenisch M, Khanal R, Hu Q, Dai Z, Li R, et al. Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model. J Hepatol 2021;75:1420-1433. https://doi.org/10.1016/J.JHEP.2021.08.011. · DOI
  134. Chand V, Pandey A, Kopanja D, Guzman G, Raychaudhuri P. Opposing roles of the forkhead box factors FoxM1 and FoxA2 in liver cancer. Mol Cancer Res 2019;17:1063-1074. https://doi.org/10.1158/1541-7786.MCR-18-0968. · DOI
  135. Yue HY, Yin C, Hou JL, Zeng X, Chen YX, Zhong W, et al. Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats. Gut 2010;59:236- 246. https://doi.org/10.1136/GUT.2008.174904. · DOI
  136. Gardin A, Remih K, Gonzales E, Andersson ER, Strnad P. Modern thera- peutic approaches to liver-related disorders. J Hepatol 2022;76:1392- 1409. https://doi.org/10.1016/J.JHEP.2021.12.015. · DOI
  137. Dalwadi DA, Torrens L, Abril-Fornaguera J, Pinyol R, Willoughby C, Posey J, et al. Liver injury increases the incidence of HCC following AAV gene therapy in mice. Mol Ther 2021;29:680-690. https://doi.org/10.1016/ J.YMTHE.2020.10.018. · DOI
  138. Reebye V, Sætrom P, Mintz PJ, Huang KW, Swiderski P, Peng L, et al. Novel RNA oligonucleotide improves liver function and inhibits liver carci- nogenesis in vivo. Hepatology 2014;59:216-227. https://doi.org/10.1002/ HEP.26669. · DOI
  139. Huang KW, Reebye V, Czysz K, Ciriello S, Dorman S, Reccia I, et al. Liver activation of hepatocellular nuclear factor-4a by small activating RNA rescues dyslipidemia and improves metabolic profile. Mol Ther Nucleic Acids 2020;19:361-370. https://doi.org/10.1016/J.OMTN.2019.10.044. · DOI
  140. Berraondo P, Martini PGV, Avila MA, Fontanellas A. Messenger RNA therapy for rare genetic metabolic diseases. Gut 2019;68:1323-1330. https://doi.org/10.1136/GUTJNL-2019-318269. · DOI
  141. Jericó D, Córdoba KM, Jiang L, Schmitt C, Morán M, Sampedro A, et al. mRNA-based therapy in a rabbit model of variegate porphyria offers new insights into the pathogenesis of acute attacks. Mol Ther Nucleic Acids 2021;25:207-219. https://doi.org/10.1016/J.OMTN.2021.05.010. · DOI
  142. Tafaleng EN, Mukherjee A, Bell A, Morita K, Guzman-Lepe J, Haep N, et al. Hepatocyte nuclear factor 4 alpha 2 messenger RNA reprograms liver-enriched transcription factors and functional proteins in end-stage cirrhotic human hepatocytes. Hepatol Commun 2021;5:1911-1926. https://doi.org/10.1002/HEP4.1763. · DOI
  143. Gadd VL, Aleksieva N, Forbes SJ. Epithelial plasticity during liver injury and regeneration. Cell Stem Cell 2020;27:557-573. https://doi.org/10. 1016/J.STEM.2020.08.016. · DOI · Paper page
  144. D'Avola D, Granito A, de la Torre-Aláez M, Piscaglia F. The importance of liver functional reserve in the non-surgical treatment of hepatocellular carcinoma. J Hepatol 2022;76:1185-1198. https://doi.org/10.1016/J.JHEP. 2021.11.013. · DOI

Cited by

Sorted by citations

  • An extended transcription factor regulatory network controls hepatocyte identity

    Dubois‐Chevalier, J., Gheeraert, C., Berthier, A., Boulet, C., Dubois, V., Guille, L., Fourcot, M., Marot, G., Gauthier, K., Dubuquoy, L., et al. (2023) · EMBO Reports · doi:10.15252/embr.202357020 · Cited by 6 · see citing works

    “We and others have established that compromised hepatocyte identity due to decreased Hep-ID TF gene expression is commonly found in severe liver injuries in both mouse models and humans (Argemi et al, 2019; Berasain et al., 2022; Bou Saleh et al, 2021; Dubois et al., 2020a; Gunewardena et al, 2022; Hyun et al, 2020; L…”
    Influential

Authors
Berasain, C., Arechederra, M., Argemí, J., Fernández-Barrena, M. G., & Avila, M. A.
Affiliations
Instituto de Salud Carlos III (ES)
Corresponding author
Berasain, Carmen
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2023-02
Volume
78
Issue
2
Pages
401-414
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2022.09.001
OpenAlex
W4295806040
Cited by
99
References
21
Citations by year
2026: 22 · 2025: 33 · 2024: 27 · 2023: 15 · 2022: 2
FWCI
3.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, cc-by-nc-nd)
Funders
  • Ministerio de Ciencia, Innovación y Universidades (10.13039.501100011033, PID2020-117116RB-I00, RYC2018-024475-1, / AEI10.13039/501100011033, PID2019, PID2020, 10.13039, .13039/501100011033, 501100011033)
  • Ministerio de Ciencia e Innovación (.13039/501100011033, 10.13039, / AEI/10, PID2019, 10.13039/501100011033/, 501100011033, RYC2018‐024475‐1, PID2020, I00/AEI/10.13039, /AEI/10.13039/ 501100011033)
  • Gobierno de Navarra (55/2018, PC082-083-084 EHGNA)
  • Instituto de Salud Carlos III (PI20/01663, /10.13039/501100011033, PI19/00163, AEI/10.13039/501100011033)
  • European Regional Development Fund (PID2020-117116RB-I00, 10.13039/501100011033, 13039/501100011033, AEI/10.13039/501100011033, 501100011033)
  • Agencia Estatal de Investigación (AEI//10.13039/501100011033/, 501100011033, 10.13039/501100011033, 13039, .13039/501100011033, 10.13039, RYC2018-024475-1, AEI/10, I00/AEI/10.13039/501100011033, PID2019)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
chronic liver disease, liver regeneration, HNF4α, transcription factors, liver dysfunction, liver cirrhosis, liver transcriptome
MeSH terms
Humans, Identity Crisis, Liver, Liver Diseases, Transcription Factors, Hepatocytes, Hepatocyte Nuclear Factor 4

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