Skip to main content
SpringerLink
Log in

Effect of Acute Ethanol Exposure on Hepatic Stimulator Substance (HSS) Levels During Liver Regeneration: Protective Function of HSS

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Ethanol administration in rats induces liver damage and suppression of liver regeneration. To further understand the underlying mechanism, we investigated the effects of ethanol on hepatic stimulator substance (HSS) levels during liver regeneration caused by partial hepatectomy. The hepatotrophic action of HSS to ethanol-treated partially hepatectomized rats was also examined. Rats received repetitive ethanol or saline doses beginning 1 hr prior to 70% partial hepatectomy (PH), and the animals were killed at 16, 24, 32, 40, 48, and 60 hr after PH. Our results showed that ethanol inhibited hepatic regenerative capacity and prolonged liver regenerative process. HSS biological activity in ethanol-administered rats peaked at 48 hr after PH, in contrast to saline-treated ones where activity peaked at 24 hr. Additionally, exogenous HSS administration to ethanol-treated partially hepatectomized rats increased liver proliferating capacity and suppressed the elevation of serum ALT activity. These results showed that ethanol modifies the time course of HSS biological activity during the regenerating process. The observed suppression of HSS activity at 24 hr after PH was in relation with a reduction of DNA synthesis. Exogenous administration of HSS to ethanol-treated partially hepatectomized rats restored DNA synthesis and ameliorated serum AST levels, indicating that HSS could be used in the treatment of ethanol-induced hepatic failures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Thurman RG: Mechanism of hepatic toxicity. II. Alcoholic liver injury involves activation of kupffer cells by endotoxin. Am J Physiol 275:G605-G611, 1998

    Google Scholar 

  2. Lieber CS: Hepatic and metabolic effects of ethanol. Pathogenesis and prevention. Ann Med 26:325-330, 1994

    Google Scholar 

  3. Bird GLA: Cytokines—mediators of acute alcoholic hepatitis. Adv Biosci 86:163-171, 1993

    Google Scholar 

  4. Lands WEM: Cellular signals in alcoh-Induced liver injury. A review Alcoholism. Clin Exp Res Exp Res 19:928-938, 1995

    Google Scholar 

  5. Par A: Pathogenesis and management of alcoholic liver injury. Acta Physiol Hung 80:325-350, 1992

    Google Scholar 

  6. Chen J, Kunos B, Gao B: Ethanol rapidly inhibits I1-6-activated STAT 3 and C/EBP mRNA expression in freshly isolated rat hepatocytes. FEBS Lett 457:162-168, 1999

    Google Scholar 

  7. Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM: Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Physiol 275:G696-G704, 1998

    Google Scholar 

  8. Zhang BH, Gong Y, Minuk GY: Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-γ1: Relevance to impaired hepatocyte proliferation. Biochem Biophys Res Commun 257:89-94, 1999

    Google Scholar 

  9. Bucher NLR, Farmer SF: Liver regeneration following partial hepatectomy: genes and metabolism. In Liver Growth and Repair. A Strain, AM Diehl (eds). London, Chapman and Hall, 1998 pp 3-27

    Google Scholar 

  10. Fausto N: Liver regeneration. J, Hepatol 32(suppl 1):19-31, 2000

    Google Scholar 

  11. Taub R, Greenbaum LE, Peng Y: Transcriptional regulatory signals define cytokine-dependent and-independent pathways in liver regeneration. Semin Liver Dis 19:117-127, 1999

    Google Scholar 

  12. Michalopoulos GK, De Frances MC: Liver regeneration. Science 276:60-66, 1997

    Google Scholar 

  13. Francavilla A, Di Leo A, Polimeno L, Gavaler J, Pellici R, Todo S, Kam I, Prelich J, Makowka L, Starzl TE: The effect of hepatic stimulatory substance, isolated from regenerating hepatic cytosol, and 50,000 and 300,000 subfractions in enhancing survival in experimental acute hepatic failure in rats treated with d-galactosamine. Hepatology 6:1346-1351, 1986

    Google Scholar 

  14. Fleig WE, Lehmann H, Wagner H, Hoss G, Ditschuneit H: Hepatic regenerative stimulator substance in the rabbit. Relation to liver regeneration after partial hepatectomy. J Hepatol 3:19-26, 1986

    Google Scholar 

  15. Gupta S, Labrecque DR, Shafritz DA: Mitogenic effects of hepatic stimulator substance on cultured nonparenchymal liver epithelial cells. Hepatology 15:485-491, 1992

    Google Scholar 

  16. Terbalache J, Porter KA, Starzl TE, Moore J, Patzelt L, Hayashida N: Stimulation of hepatic regeneration after partial hepatectomy by infusion of a cytosol extract from regeneration dog liver. Surg Gynecol Obstet 151:538-544, 1980

    Google Scholar 

  17. Kahn D, Hickman R, Terblanche J, Kirch RE: Hepatic stimulator substance in extracts from regenerating porcine liver. Eur Surg Res 20:168-174, 1988

    Google Scholar 

  18. Gupta S: Hepatic growth factors:progress and perspectives In Curent Hepatology. GL Gitnick (ed). Chicago, Mosby Yearbooks, 1992, pp 75-130

    Google Scholar 

  19. Labrecque DR: Hepatic stimulator substance: Discovery, characteristics and mechanisms of action. Dig Dis Sci 36:669-673, 1991

    Google Scholar 

  20. Hagiya M, Francavilla A, Polimeno L, Ihara I, Sakai H, Seki T, Simonishi M, Porter KA, Sarzl TE: Cloning and sequence analysis of rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demostration of tissue distribution. Proc Natl Acad Sci USA 91:8142-8146, 1994

    Google Scholar 

  21. Gandhi CR, Kuddus R, Subbotin H, Prelich J, Murase N, Rao AS, Nalesnik MA, Watkins SC, Deleo A, Trucco M, Starzl TE: A fresh look of augmenter of liver regeneration in rats. Hepatology 29:1435-1445, 1999

    Google Scholar 

  22. Zhang BH, Gong DZ, Mei MH: Protection of regeneration liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: role of hepatic stimulator substance. J Gastroenterol-Hepatol 14:1010-1017, 1999

    Google Scholar 

  23. An W, Liu XJ, Lei TG, Dai J, Du GG: Growth induction of hepatic stimulator substance in hepatocytes through ist regulation on EGF receptors. Cell Res 9:37-49, 1999

    Google Scholar 

  24. Mei MH, An W, Zhang BH, Shao Q, Gong DZ: Hepatic stimulator substance protects against acute liver failure induced by carbon tetrachloride poisoning in mice. Hepatology 17:638-644, 1993

    Google Scholar 

  25. Yao Z, Yang W, Zhang W, Chen Y, Yang F: Human hepatic regenerative stimulator substance: partial purification and biological characterization of hepatic stimulator substance from human fetal liver cells. Hepatology 12:1144-1151, 1990

    Google Scholar 

  26. Theocharis SE, Margeli A, Spiliopoulou C, Skaltsas S, Kittas C, Koutselinis A: Hepatic stimulator substance administration enhances the regenerative capacity of hepatocytes in cadmium-pretreated partially hepatectomized rats. Dig Dis Sci 41:1475-1480, 1996

    Google Scholar 

  27. Margeli AP, Theocharis SE, Spilopoulou C, Horti M, Koutselinis A: Hepatic Stimulator substance administration affects cadmium-induced hepatotoxicity in the rat. Int Hepatol Commun 5:128-134, 1996

    Google Scholar 

  28. Theocharis SE, Margeli AP, Agapitos EV, Mykoniatis MG, Kittas CN, Davaris PS: Effect of hepatic stimulator substance administration on tissue regeneration due to thioacetamide-induced liver injury in rats. Scand J Gastroenterol 33:656-663, 1998

    Google Scholar 

  29. Kyprianidis KG, Mykoniatis MG, Papadimitriou DG, Valsamidou A: Effect of subtotal pancreatectomy on the rate of liver regeneration: role of the hepatic stimulator substance. J Surg Res 62:267-272, 1996

    Google Scholar 

  30. Margeli AP, Skaltsas SD, Spiliopoulou CA, Mykoniatis MG, Theocharis SE: Hepatic stimulator substance activity in the liver of thioacetamide-intoxicated rats. Liver 19:519-525, 1999

    Google Scholar 

  31. Liakos AA, Mykoniatis MG, Kokala ME, Papadimitriou DG, Liatsos GD: Levels of hepatic stimulator substance in the liver regenerating process of partially hepatectomized rats pretreated with a single dose of carbon tetrachloride. Dig Dis Sci 44:1046-1053, 1999

    Google Scholar 

  32. Higgins GM, Anderson RM: Experimental pathology of the liver. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 12:186-202, 1931

    Google Scholar 

  33. Munro HN, Fleck A: Recent developments in the measurement of nucleic acids in biological materials. Analyst 91:78-88, 1966

    Google Scholar 

  34. Richards GMG: Modifications of the diphenylamine reaction giving increased sensitivity and simplicity in the estimation of DNA. Anal Biochem 37:369-376, 1974

    Google Scholar 

  35. Kahn D, Sranas GM, Eagon PK, Makowka L, Podesta L, Chapchad P, Starzl TE, Van Thiel DH: Effect of an antiandrogenic H2 receptor antagonist on hepatic regeneration in rats. J Lab Clin Med 112:232-239, 1988

    Google Scholar 

  36. Lowry OH, Rosebrough NJ, Farr AL, Randall Rj: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-275, 1951

    Google Scholar 

  37. Miller N: Protein determination for large numbers of samples. Anal Chem 31:964, 1959

    Google Scholar 

  38. Labrecque DR, Bachur NR: Hepatic stimulator substance: physicochemical characteristics and specificity. Am J Physiol 242:G281-G288, 1982

    Google Scholar 

  39. Labrecque DR, Pesch LA: Preparation and partial characterisation of hepatic regenerative stimulator substance (SS) from rat liver. J Physiol 248:273-284, 1975

    Google Scholar 

  40. Frank WO, Rayyes AN, Washington A, Holt PR: Effect of acute ethanol administration upon hepatic regeneration. J Lab Clin Med 93:402-413, 1979

    Google Scholar 

  41. Wands JR, Carter EA, Bucher NLR, Isselbacher KJ: Inhibition of hepatic regeneration in rats by acute and chronic ethanol intoxication. Gastroenterology 77:528-531, 1979

    Google Scholar 

  42. Orrego H, Crossley IR, Saldivia V, Medline A, Varghese G, Israel Y: Long-term ethanol administration and short-and long-term liver regeneration after partial hepatectomy. J Lab Clin Med 97:221-230, 1981

    Google Scholar 

  43. Duguay L, Coutu D, Hetu C, Joly J-G: Inhibition of liver regeneration by chronic alcohol administration. Gut 23:8-13, 1982

    Google Scholar 

  44. Takada A, Nei J, Tamino H, Shujiro T: Effects of malotilate on ethanol-inhibited hepatocyte regeneration in rats. J Hepatol 5:336-343, 1987

    Google Scholar 

  45. Tanaka T, Nishiguchi S, Kuroki T, Kobayashi K, Matsui-Yuasa I, Otani S, Toda T, Monna T, Sukegawa Y: Effects of single ethanol administration on hepatic ornithine decarboxylase induction and polyamine metabolism. Hepatology 14:696-700, 1991

    Google Scholar 

  46. Yoshida Y, Komatsou M, Ozeki A, Nango R, Tsukamoto I: Ethanol represses thymidylate syntheses and thymidine kinase at mRNA level in regenerating rat liver after partial hepatectomy. Biochim Biophys Acta 1336:180-186, 1997

    Google Scholar 

  47. Zhang BH, Ho V, Farell GC: Specific involvement of Galpha;i2 with epidermal growth factor receptor signaling in rat hepatocytes, and the inhibitory effect of chronic ethanol. Biochem Pharmacol 61:1021-1027, 2001

    Google Scholar 

  48. Zhang M, Gong Y, Corbin I, Mellon A, Choy P, Uhanova J, Minuk GY: Light ethanol consumption enhances liver regeneration after partial hepatectomy in rats. Gastroenterology 119(5):1333-1339, 2000

    Google Scholar 

  49. Zhang MN, Gong Y, Minuk GY: The effects of acute ethanol exposure on inhibitors of hepatic regenerative activity in the rat. Mol Cell Biochem 207:109-114, 2000

    Google Scholar 

  50. Tsukamoto I, Tanigushi Y, Miyoshi K, Kojio S: Purification and characterization of thymidine kinase from regenerating rat liver. Biochem Biophys Acta 1079:348-352, 1991

    Google Scholar 

  51. Moralez-Gonzalez JA, Gutierrez-Salinas J, Yamez L, Villagonez-Rico C, Badillo-Romero J, Hermandez-Munoz R: Morphological and biochemical effects of a low ethanol dose on rat liver regeneration. Role of route and timing of administration. Dig Dis Sci 44:1963-1974, 1999

    Google Scholar 

  52. Assy N, Minuk GY: Liver regeneration: methods for monitoring and their applications. J Hepatol 26:945-952, 1997

    Google Scholar 

  53. Fleig WE, Hoss G: Partial purification of rat hepatic stimulator substance and characterization of its action on hepatoma cells and normal hepatocytes. Hepatology 9:240-248, 1989

    Google Scholar 

  54. Labrecque DR, Steel G, Fogerty S, Wilson M, Barton J: Purification and physical-chemical characterization of hepatic stimulator substance. Hepatology 7:100-106, 1987

    Google Scholar 

  55. Labrecque DR: In vitro stimulation of cell growth by hepatic stimulator substance. Am J Physiol 242:G289-G295, 1982

    Google Scholar 

  56. Margeli AP, Manolis E, Skaltsas SN, Tsarpalis KS, Mykoniatis MG, Theocharis SE: Hepatic stimulator substance activity in an animal model of fulminant hepatic failure and encephalopathy. Dig Dis Sci 47:2170-2178, 2002

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Department of Experimental Pharmacology, Medical School, University of Athens, Mikras Asias 75, GR 11527, Athens, Greece

    George D. Liatsos, Michael G. Mykoniatis, Alexandra Margeli, Aristotelis A. Liakos & Stamatios E. Theocharis

Authors
  1. George D. Liatsos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael G. Mykoniatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandra Margeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aristotelis A. Liakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stamatios E. Theocharis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael G. Mykoniatis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liatsos, G.D., Mykoniatis, M.G., Margeli, A. et al. Effect of Acute Ethanol Exposure on Hepatic Stimulator Substance (HSS) Levels During Liver Regeneration: Protective Function of HSS. Dig Dis Sci 48, 1929–1938 (2003). https://doi.org/10.1023/A:1026157901805

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026157901805

Search

Navigation