Startseite The impact of steatosis on liver regeneration
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

The impact of steatosis on liver regeneration

  • Manon Allaire und Hélène Gilgenkrantz EMAIL logo
Veröffentlicht/Copyright: 21. November 2018
Veröffentlichen auch Sie bei De Gruyter Brill
Manuskript einreichen Informationen für Autor*innen
Hormone Molecular Biology and Clinical Investigation
Aus der Zeitschrift Hormone Molecular Biology and Clinical Investigation Band 41 Heft 1

Abstract

Alcoholic and non-alcoholic fatty liver diseases are the leading causes of cirrhosis in Western countries. These chronic liver diseases share common pathological features ranging from steatosis to steatohepatitis. Fatty liver is associated with primary liver graft dysfunction, a higher incidence of complications/mortality after surgery, in correlation with impaired liver regeneration. Liver regeneration is a multistep process including a priming phase under the control of cytokines followed by a growth factor receptor activation phase leading to hepatocyte proliferation. This process ends when the initial liver mass is restored. Deficiency in epidermal growth factor receptor (EGFR) liver expression, reduced expression of Wee1 and Myt1 kinases, oxidative stress and alteration in hepatocyte macroautophagy have been identified as mechanisms involved in the defective regeneration of fatty livers. Besides the mechanisms, we will also discuss in this review various treatments that have been investigated in the reversal of the regeneration defect, for example, omega-3 fatty acids, pioglitazone, fibroblast growth factor (FGF)19-based chimeric molecule or growth hormone (GH). Since dysbiosis impedes liver regeneration, targeting microbiota could also be an interesting therapeutic approach.

Keywords: fatty liver disease; liver regeneration; steatosis

  1. Author Statement

  2. Research funding: Authors state no funding was involved.

  3. Conflict of interest: The authors do not have conflicts of interest to declare.

  4. Informed consent: Informed consent is not applicable.

  5. Ethical approval: The conducted research is not related to either human or animals use.

References

[1] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal A. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22.10.1038/s41591-018-0104-9Suche in Google Scholar PubMed PubMed Central

[2] Gilgenkrantz H, Collin de l’Hortet A. Understanding liver regeneration: from mechanisms to regenerative medicine. Am J Pathol. 2018;188:1316–27.10.1016/j.ajpath.2018.03.008Suche in Google Scholar PubMed

[3] Wang B, Zhao L, Fish M, Logan CY, Nusse R. Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature. 2015;524:180–5.10.1038/nature14863Suche in Google Scholar PubMed PubMed Central

[4] Forbes SJ, Newsome PN. Liver regeneration-mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol. 2016;13:473–85.10.1038/nrgastro.2016.97Suche in Google Scholar PubMed

[5] Crumm S, Cofan M, Juskeviciute E, Hoek JB. Adenine nucleotide changes in the remnant liver: an early signal for regeneration after partial hepatectomy. Hepatology. 2008;48:898–908.10.1002/hep.22421Suche in Google Scholar PubMed PubMed Central

[6] Huang W, Ma K, Zhang J, Qatani M, Cuvillier J, Liu J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312:233–6.10.1126/science.1121435Suche in Google Scholar PubMed

[7] Zhang L, Wang YD, Chen WD, Wang X, Lou G, Liu N, et al. Promotion of liver regeneration repair by farnesoid X receptor in both liver and intestine in mice. Hepatology. 2012;56:2336–43.10.1002/hep.25905Suche in Google Scholar PubMed PubMed Central

[8] Padrissa-Altes S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Bohm F, et al. Control of hepatocyte proliferation and survival by FGF receptors is essential for liver regeneration in mice. Gut. 2015;64:1444–53.10.1136/gutjnl-2014-307874Suche in Google Scholar PubMed

[9] Francés DE, Ronco MT, Ingaramo PI, Monti JA, Pisani GB, Parody JP, et al. Role of reactive oxygen species in the early stages of liver regeneration in streptozotocin-induced diabetic rats. Free Radic Res. 2011;45:1143–53.10.3109/10715762.2011.602345Suche in Google Scholar PubMed

[10] Shteyer E, Liao Y, Muglia LJ, HruZ PW, Rudnick DA. Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice. Hepatology. 2004;40:1322–32.10.1002/hep.20462Suche in Google Scholar PubMed

[11] Gual P, Gilgenkrantz H, Lotersztajn S. Autophagy in chronic liver diseases: the two faces of Janus. Am J Physiol Cell Physiol. 2017;312:C263–73.10.1152/ajpcell.00295.2016Suche in Google Scholar PubMed

[12] Jörs S, Jeliazkova P, Ringelhan M, Thalhammer J, Dürl S, Ferrer J, et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest. 2015;125:2445–57.10.1172/JCI78585Suche in Google Scholar PubMed PubMed Central

[13] Rokusz A, Veres D, Szucs A, Bugik E, Mozes M, Paku S, et al. Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models. Plos One. 2017;12:e0176518.10.1371/journal.pone.0176518Suche in Google Scholar PubMed PubMed Central

[14] Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-tetri BA, Bhathal PS, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133:80–90.10.1053/j.gastro.2007.05.012Suche in Google Scholar PubMed

[15] Raven A, Lu WY, Man TY, Ferrreira-Gonzalez S, O’Duibhir E, Dwyer BJ, et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature. 2017;547:350–4.10.1038/nature23015Suche in Google Scholar PubMed PubMed Central

[16] De Meijer VE, Kalish BT, Puder M, Ijzermans JN. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;97:1331–9.10.1002/bjs.7194Suche in Google Scholar PubMed

[17] Truant S, Bouras AF, Petrovai G, Buob D, Ernst O, Boleslawski E, et al. Volumetric gain of the liver after major hepatectomy in obese patients. Ann Surg. 2013;5:696–704.10.1097/SLA.0b013e3182a61a22Suche in Google Scholar PubMed

[18] Kele PG, Van der Jagt E, Gouw AS, Lisman T, Porte RJ, De Boer MT. The impact of hepatic steatosis on liver regeneration after partial hepatectomy. Liver Intern. 2013;33:469–75.10.1111/liv.12089Suche in Google Scholar PubMed

[19] Cho JY, Suh KS, Kwon CH, Yi NJ, Lee KU. Mild hepatic steatosis is not a major risk factor for hepatectomy and regenerative power is not impaired. Surgery. 2006;139:508–15.10.1016/j.surg.2005.09.007Suche in Google Scholar PubMed

[20] Kaibori M, Ha-Kawada SK, Uchida Y, Ishizaki M, Saito T, Matsui K, et al. Liver regeneration in donors evaluated by tc-99m-GSA scintigraphy after living donor transpantation. Dig Dis Sci. 2008;53:850–5.10.1007/s10620-007-9902-5Suche in Google Scholar PubMed

[21] Picard C, Lambotte L, Starkel P, Sempoux C, Saliez A, Van den Berge V, et al. Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats. J Hepatol. 2002;36:645–52.10.1016/S0168-8278(02)00038-7Suche in Google Scholar

[22] Garnol T, Kucera O, Stankova P, Lotkova H, Cervinkova Z. Does simple steatosis affect liver regeneration after partial hepatectomy in rats? Acta Medica. 2016;59:35–42.10.14712/18059694.2016.87Suche in Google Scholar

[23] Newberry EO, Kennedy SM, Xie Y, Luo J, Stanley SE, Semenkovich CF. Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models. Hepatology. 2008;48:1097–105.10.1002/hep.22473Suche in Google Scholar

[24] Yang SQ, Lin HZ, Mandal AK, Huang J, Diehl AM. Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology. Hepatology. 2001;34:694–706.10.1053/jhep.2001.28054Suche in Google Scholar

[25] Leclercq IA, Field J, Farrell GC. Leptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury. Gastroenterology. 2003;124:1451–64.10.1016/S0016-5085(03)00270-1Suche in Google Scholar

[26] DeAngelis RA, Markiewski MM, Taub R, Lambris JD. A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. Hepatology. 2005;42:1148–57.10.1002/hep.20879Suche in Google Scholar PubMed

[27] Collin de l’Hortet A, Zerrad-Saadi A, Prip-Buus C, Fauveau V, Helmy N, Ziol M, et al. GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency. Endocrinology. 2014;155:2545–54.10.1210/en.2014-1010Suche in Google Scholar PubMed

[28] Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest. 2015;125:981–92.10.1172/JCI73957Suche in Google Scholar PubMed PubMed Central

[29] Toshima T, Shirabe K, Fukuhara T, Ikegami T, Yoshizumi T, Soejima Y, et al. Suppression of autophagy during liver regeneration impairs energy charge and hepatocyte senescence in mice. Hepatology. 2014;60:290–300.10.1002/hep.27140Suche in Google Scholar PubMed

[30] Spahr L, Lambert JF, Rubbia-Brandt L, Chalandon Y, Frossard JL, Giostra E, et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology. 2008;48:221–9.10.1002/hep.22317Suche in Google Scholar PubMed

[31] Meng F, Francis H, Glaser S, Han Y, DeMorrow S, Stokes A, et al. Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration. Hepatology. 2012;55:209–21.10.1002/hep.24673Suche in Google Scholar PubMed PubMed Central

[32] Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I. Randomized placebo-controlled trial of pioglitazone in nondiabetic subjects with non-alcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.10.1053/j.gastro.2008.06.047Suche in Google Scholar PubMed

[33] Aoyama T, Ikejima K, Kon K, Okumara K, Arai K, Watanabe S. Pioglitazone promotes survival and prevents hepatic regeneration failure following partial hepatectomy in obese and diabetic KK-Ay mice. Hepatology. 2009;49:1636–44.10.1002/hep.22828Suche in Google Scholar PubMed

[34] Marsman HA, de Graaf W, Heger M, van Golen RF, Ten Kate FJ, Bennink R, et al. Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids. Br J Surg. 2013;100:674–83.10.1002/bjs.9059Suche in Google Scholar PubMed

[35] Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399–408.10.1016/j.jhep.2015.08.038Suche in Google Scholar PubMed PubMed Central

[36] Valdecantos MP, Pardo V, Ruiz L, Castro-Sanchez L, Lanzon B, Fernandez-Millan E, et al. A novel glucagon-like peptide1/Glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology. 2017;65:950–68.10.1002/hep.28962Suche in Google Scholar PubMed

[37] Alvarez-Sola G, Uriarte I, Latasa MU, Fernandez-Barrena MG, Urtasun R, Elizalde M, et al. Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration. Gut. 2017;66:1818–28.10.1136/gutjnl-2016-312975Suche in Google Scholar PubMed

[38] Gupta P, Venugopal SK. Augmenter of liver regeneration: a key protein in liver regeneration and pathophysiology. Hepatol Res. 2018;48:587–96.10.1111/hepr.13077Suche in Google Scholar PubMed

[39] Inaba Y, Furutani T, Kimura K, Watanabe H, Haga S, Kido Y, et al. Growth arrest and DNA damage-inducible 34 regulates liver regeneration in hepatic steatosis in mice. Hepatology. 2015;61:1343–56.10.1002/hep.27619Suche in Google Scholar PubMed

[40] Liu HX, Keane R, Sheng L, Wan YJ. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015;63:1502–10.10.1016/j.jhep.2015.08.001Suche in Google Scholar PubMed PubMed Central

Received: 2018-07-13
Accepted: 2018-10-11
Published Online: 2018-11-21

©2020 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Special Issue: ‘Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights’ / Editors: Gérard S. Chetrite and Bruno Féve
  2. Editorial Preface
  3. Preface to special issue on “Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights”
  4. Original Article
  5. Aromatase in normal and diseased liver
  6. Review Articles
  7. Hepatocellular carcinoma in the context of non-alcoholic steatohepatitis (NASH): recent advances in the pathogenic mechanisms
  8. Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models
  9. Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis
  10. Hypothyroidism and nonalcoholic fatty liver disease – a chance association?
  11. Mini-Review Article
  12. The impact of steatosis on liver regeneration
  13. Regular Issue
  14. Original Articles
  15. Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats
  16. 3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line
  17. Machine learning as new promising technique for selection of significant features in obese women with type 2 diabetes
  18. Implementation of a novel self-induced promoter for the expression of pharmaceutical peptides in Escherichia coli: YY(3-36) peptide
  19. Comparison of the effect of 12- and 24-session cardiac rehabilitation on physical, psychosocial and biomedical factors in ischemic heart disease patients
  20. The stimulation protocol in poor responder IVF; a minimal or high-dose stimulation? – A meta-analysis
  21. Review Articles
  22. Cell free DNA: revolution in molecular diagnostics – the journey so far
  23. Genitourinary syndrome of menopause (GSM) and laser VEL: a review
https://doi.org/10.1515/hmbci-2018-0050
Schlagwörter für diesen Artikel
fatty liver disease; liver regeneration; steatosis

Artikel in diesem Heft

  1. Special Issue: ‘Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights’ / Editors: Gérard S. Chetrite and Bruno Féve
  2. Editorial Preface
  3. Preface to special issue on “Liver Metabolic Diseases and Hepatocellular Carcinoma: New Hormonal and Clinical Insights”
  4. Original Article
  5. Aromatase in normal and diseased liver
  6. Review Articles
  7. Hepatocellular carcinoma in the context of non-alcoholic steatohepatitis (NASH): recent advances in the pathogenic mechanisms
  8. Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models
  9. Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis
  10. Hypothyroidism and nonalcoholic fatty liver disease – a chance association?
  11. Mini-Review Article
  12. The impact of steatosis on liver regeneration
  13. Regular Issue
  14. Original Articles
  15. Hepatoprotective effects of Shilajit on high fat-diet induced non-alcoholic fatty liver disease (NAFLD) in rats
  16. 3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line
  17. Machine learning as new promising technique for selection of significant features in obese women with type 2 diabetes
  18. Implementation of a novel self-induced promoter for the expression of pharmaceutical peptides in Escherichia coli: YY(3-36) peptide
  19. Comparison of the effect of 12- and 24-session cardiac rehabilitation on physical, psychosocial and biomedical factors in ischemic heart disease patients
  20. The stimulation protocol in poor responder IVF; a minimal or high-dose stimulation? – A meta-analysis
  21. Review Articles
  22. Cell free DNA: revolution in molecular diagnostics – the journey so far
  23. Genitourinary syndrome of menopause (GSM) and laser VEL: a review
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 29.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hmbci-2018-0050/html
Button zum nach oben scrollen