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Review article: Biomedical intelligence

Vol. 142 No. 1516 (2012)

The emerging role of serotonin in liver regeneration

  • George K Papadimas
  • Konstantinos N Tzirogiannis
  • Michael G Mykoniatis
  • Agni D Grypioti
  • Georgia A Manta
  • Georgios I Panoutsopoulos
DOI
https://doi.org/10.4414/smw.2012.13548
Cite this as:
Swiss Med Wkly. 2012;142:w13548
Published
08.04.2012

Summary

Serotonin has a multifunctional role in many different organs serving either as a neurotransmitter in the central nervous system or a paracrine factor in the gastrointestinal tract. Over 90% of serotonin is synthesised in the enterochromaffin cells of the intestine and subsequently taken up by platelets. The involvement of platelet-derived serotonin in liver mass restoration after partial hepatectomy or toxic injury has been greatly investigated during the last decade. There is a growing body of evidence implicating serotonin in hepatic regeneration through altered expression of serotonin receptor subtypes in the liver. This review article provides a brief overview on the current knowledge about the actions of serotonin in liver regeneration.

References

  1. Riehle KJ, Dann YY, Campbell JS, Fausto N. New concepts in liver regeneration. J Gastroenterol Hepatol. 2011;26(Suppl.1):203–12.
  2. Fausto N, Kampbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–53.
  3. Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213:286–300.
  4. Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176:2–13.
  5. Cruise JL, Knechtle SJ, Bollinger RR, Kuhn C, Michalopoulos G. Alpha 1-adrenergic effects and liver regeneration. Hepatology. 1987;7:1189–94.
  6. Cruise JL, Houck KA, Michalopoulos GK. Induction of DNA synthesis in cultured rat hepatocytes through stimulation of a1 adrenoreceptor by norepinephrine. Science. 1985;227:749–51.
  7. Cruise JL. Alpha 1-adrenergic receptors in liver regeneration. Dig Dis Sci. 1991;36:485–8.
  8. Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. 2003;4:1002–12.
  9. Berger M. Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.
  10. Fuller RW, Wong DT. Serotonin uptake and serotonin uptake inhibition. Ann N Y Acad Sci. 1990;60:68–78.
  11. Jonnakuty C, Gragnoli C. What do we know about serotonin? J Cell Physiol. 2008;217:301–6.
  12. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety. 2000;12(Suppl. 1):2–19.
  13. Mendelson WB. Neurotransmitters and sleep. J Clin Psychiatry. 2001;62(Suppl.10):5–8.
  14. Lam DD, Garfield AS, Marston OJ, Shaw J, Heisler LK. Brain serotonin system in the coordination of food intake and body weight. Pharmacol Biochem Behav. 2010;97:84–91.
  15. Gershon MD, Tack J. The serotonin signalling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.
  16. Mercado CP, Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010;10:231–41.
  17. Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J. 2010;74:597–607.
  18. Lesurtel M, Soll C, Graf R, Clavien PA. Role of serotonin in the hepato-gastrointestinal tract: an old molecule for new perspectives. Cell Mol Life Sci. 2008;65:940–52.
  19. Clavien PA. Liver regeneration: a spotlight on the novel role of platelets and serotonin. Swiss Med Wkly. 2008;138:361–70.
  20. Ruddell RG, Mann DA, Ramm GA. The function of serotonin within the liver. J Hepatol. 2008;48:666–75.
  21. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–152.
  22. Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31.
  23. Michalopoulos GK, Defrances MC. Liver regeneration. Science 1997;276:60–5.
  24. LaBrecque D. Liver regeneration: a picture emerges from the puzzle. Am J Gastroenterol. 1994;89:586–97.
  25. Mangnall D, Bird NC, Majeed AW. The molecular physiology of liver regeneration following partial hepatectomy. Liver Int. 2003;23:124–38.
  26. Marubashi S, Sakon M, Nagano H, Gotoh K, Hashimoto K, Kubota M, et al. Effect of portal hemodynamics on liver regeneration studied in a novel portohepatic shunt rat model. Surgery. 2004;136:1028–37.
  27. Fausto N, Laird AD, Webber EM. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 1995;9:1527–36.
  28. Tian ZJ, An W. ERK1/2 contributes negative regulation to STAT3 activity in HSS-transfected HepG2 cells. Cell Res. 2004;14:141–7.
  29. Talarmin H, Rescan C, Cariou S, Glaise D, Zanninelli G, Bilodeau M, et al. The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of G1 phase progression in proliferating hepatocytes. Mol Cell Biol. 1999;19:6003–11.
  30. Balasubramanian S, Paulose CS. Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: possible involvement of serotonin S2 receptor. Hepatology. 1998;27:62–6.
  31. Persson B, Heykants J, Hedner T. Clinical pharmacokinetics of ketanserin. Clin Pharmacokinet. 1991;20:263–79.
  32. Liu Y, Zhang ZY. Serotonin receptor agonist quipazine promotes proliferation and apoptosis of human hepatocyte strain of L-02 strain. Hepatobiliary Pancreat Dis Int. 2009;8:278–81.
  33. Bonhaus DW, Bach C, DeSouza A, Salazar FH, Matsuoka BD, Zuppan P, et al. The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol. 1995;115:622–8.
  34. Nebiqil CG, Etienne N, Schaerlinger B, Hickel P, Launay JM, Maroteaux L. Developmentally regulated serotonin 5-HT2B receptors. Int J Dev Neurosci. 2001;19:365–72.
  35. Papadimas GK, Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Skaltsas SD, Hereti RI, et al. Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver. Liver Int. 2006;26:352–61.
  36. Sulaiman P, Joseph B, Kaimal SB, Paulose CS. Decreased hepatic 5-HT1A receptors during liver regeneration and neoplasia in rats. Neurochem Res. 2008;33:444–9.
  37. Nagao Y, Akahoshi T, Kamori M, Uehara H, Hashimoto N, Kinjo N, et al. Liver regeneration is promoted by increasing serotonin content in rat liver with secondary biliary cirrhosis. Hepatol Res. 2011;41:784–94.
  38. Murata S, Ohkohchi N, Matsuo R, Ikeda O, Myronovych A, Hoshi R. Platelets promote liver regeneration in early period after hepatectomy in mice. World J Surg. 2007;31:808–16.
  39. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science. 2006;312:104–7.
  40. Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, et al. Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2009;296:G963–8.
  41. Tian Y, Graf R, El-Badry AM, Lesurtel M, Furrer K, Moritz W, et al. Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice. Hepatology. 2011;53:253–60.
  42. Schoeffter P, Ullmer C, Gutierrez M, Weitz-Schmidt G, Lubbert H. Functional serotonin 5-HT1D receptors and 5-HT1D beta receptor mRNA expression in human umbilical vein endothelial cells. Naunyn Schmiededergs Arch Pharmacol. 1995;352:580–2.
  43. Asada M, Ebihara S, Yamanda S, Niu K, Okazaki T, Sora I, et al. Depletion of serotonin and selective inhibition of 2B receptor suppressed tumor angiogenesis by inhibiting endothelial nitric oxide synthase and extracellular signal-regulated kinase ½ phosphorylation. Neoplasia. 2009;11:408–17.
  44. Ruiz-Perez MV, Sanchez-Jimenez F, Quesada AR, Medina MA. A re-evaluation of the mitogenic effect of serotonin on vascular endothelial cells. J Biol Regul Homeost Agents. 2011;25:13–20.
  45. Lesurtel M, Soll C, Humar B, Clavien PA. Serotonin: A double-edged sword for the liver? Surgeon. 2011;ahead of print.
  46. Grueb M, Rohrbach JM, Schlote T, Mielke J. Serotonin (5-HT7) receptor-stimulated activation of cAMP-PKA pathway in bovine corneal epithelial and endothelial cells. Ophthalmic Res. 2012;48:22–7.
  47. Frampton GA, Li H, Ramirez J, Mohamad A, Demorrow S. Biogenic amines serotonin and dopamine regulate cholangiocyte hyperplastic and neoplastic growth. World J Gastrointest Pathopsysiol. 2010;1:63–8.
  48. Marzioni M, Glaser S, Francis H, Marucci L, Benedetti A, Alvaro D, et.al. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology. 2005;128:121–37.
  49. Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, Ramm GA, et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol. 2006;169:861–76.
  50. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Psysiol Rev. 2008;88:125–72.
  51. Wallace K, Burt AD, Wright MC. Liver Fibrosis. Biochem J. 2008;411:1–18.
  52. Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology. 2005;128:33–42.
  53. Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver growth. Semin Cell Dev Biol. 2002;13:425–31.
  54. Pyroja S, Joseph B, Paulose CS. Increased 5-HT2C receptor binding in the brain stem and cerebral cortex during liver regeneration and hepatic neoplasia in rats. J Neurol Sci. 2007;254:3–8.
  55. Walther DJ, Peter JU, Winter S, Holtje M, Paulmann N, Grohmann M, et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alha-granule release. Cell. 2003;115:851–62.
  56. Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 2009;7:e1000229.
  57. Guilluy C, Eddahibi S, Agard C, Guignabert C, Izikki M, Tu L, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med. 2009;179:1151–8.
  58. Liu Y, Wei L, Laskin DL, Fanburg BL. Role of protein transamidation in serotonin-induced proliferation and migration of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2011;44:548–55.
  59. Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatoheptitis. Gastroenterology. 2007;133:608–18.
  60. Beaudry P, Hadengue A, Callebert J, Gaudin C, Soliman H, Moreau R, et al. Blood and plasma 5-hydroxytryptamine levels in patients with cirrhosis. Hepatology. 1994;20:800–3.
  61. Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, et al. Stimulating healthy tissue regeneration by targeting the 5-HT2B receptor in chronic liver disease. Nat Med. 2011;17:1668–73.
  62. Soll C, Jang JH, Riener MO, Moritz W, Wild PJ, Graf R, et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology. 2010;51:1244–54.
  63. Murata R, Hamada N, Nakamura N, Kobayashi A, Fukueda M, Taira A, et al. Serotonin activity and liver dysfunction following hepatic ischemia and reperfusion. In Vivo. 2003;17:567–72.
  64. Tzirogiannis KN, Demonakou MD, Papadimas GK, Skaltsas SD, Manta GA, Kourentzi KT, et al. Effect of 5-HT2 receptor blockade on cadmium-induced acute toxicity. Dig Dis Sci. 2007;52:2351–8.