Toxicologic Pathology

 

Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Click here to sign up for SAGE Journal Email Alerts today!

Sign In to gain access to subscriptions and/or personal tools.
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Apte, U. M.
Right arrow Articles by Ramaiah, S. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Apte, U. M.
Right arrow Articles by Ramaiah, S. K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Toxicologic Pathology, Vol. 32, No. 5, 567-576 (2004)
DOI: 10.1080/01926230490508812

Hepatocyte Proliferation is the Possible Mechanism for the Transient Decrease in Liver Injury During Steatosis Stage of Alcoholic Liver Disease

Udayan M. Apte

Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A & M University, College Station, Texas 77843-4467, USA

Rachel Mcree

Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A & M University, College Station, Texas 77843-4467, USA

Shashi K. Ramaiah

Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A & M University, College Station, Texas 77843-4467, USA, sramaiah{at}cvm.tamu.edu

Steatosis is a frequent pathologic stage in alcoholic liver disease (ALD). Although the mechanisms for increased susceptibility of steatotic liver to injury have been postulated, the ability of these hepatocytes to proliferate and withstand injury is unknown. There are conflicting reports on the status of hepatocyte regeneration following chronic alcohol ingestion. Hence, the objective of this study was to investigate the temporal dynamics between the pattern of liver injury and hepatocyte proliferation during the steatosis stage of ALD. Alcoholic steatosis was induced in male Sprague—Dawley rats by feeding an ethanol (EtOH)-containing Lieber-DeCarli liquid diet for a period of 5 weeks. Microvesicular steatosis was evident in H&E sections by three weeks in the EtOH-treated rats, which further developed into panlobular macrovesicular steatosis by 5 weeks. Plasma transaminase activities indicated progressive increase in liver injury peaking at 3 weeks with significant but mild decrease at 4 and 5 weeks. CYP2E1 protein and activity was significantly increased in EtOH-fed rats as measured by Western blot and pNP hydroxylation assay. PCNA analysis of liver sections indicated that EtOH-treated rats had a significantly higher number of cells in S phase of cell division at weeks 1 (3.20 ± 0.19), 2 (7.03 ± 0.92), and 3 (4.23 ± 1.41) when compared to controls (1.5 ± 0.22). NF-{kappa}B DNA binding and Cyclin D1 proteins increased significantly in the EtOH-treated rats corresponding with enhanced hepatic proliferation. These data suggest the transient decline in liver injury during alcoholic steatosis is due to enhanced NF-{kappa}B-dependent hepatocyte proliferation.

Key Words: Apoptosis • alcoholic steatosis • CYP2E1 • Cyclin D1 • liver regeneration • liver injury • NF-{kappa}B.

References

  • Apte, U.M., Limaye, P.B., Ramaiah, S.K., Vaidya, V.S., Bucci, T.J., Warbritton, A., and Mehendale, H.M. (2002). Upregulated promitogenic signaling via cytokines and growth factors: potential mechanism of robust liver tissue repair in calorie-restricted rats upon toxic challenge. Toxicol Sci 69, 448— 59.[Abstract/Free Full Text]
  • Armbrust, T., Batusic, D., Xia, L., and Ramadori, G. (2002). Early gene expression of hepatocyte growth factor in mononuclear phagocytes of rat liver after administration of carbon tetrachloride. Liver 22, 486—94.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Arteel, G.E. (2003). Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 24, 778—90.
  • Bathgate, A.J., and Simpson, K.J. (2002). Alcoholic fatty liver. In EtOH and The Liver Mechanisms and Management (D. I. N. Sherman, V. Preedy, and R. R. Watson, eds.), pp. 3—20. Taylor and Francis, London and New York.
  • Baykov, I., Jarvelainen, H., and Lindros, K. (2003). L-Cartinite alleviates alcohol-induced liver damage in rats: role of tumor necrosis factor-alpha. Alcohol & Alcoholism 38, 400—06.[Abstract/Free Full Text]
  • Bhagwandeen, B.S., Apte, M., Manwarring, L., and Dickeson, J. (1987). Endotoxin induced hepatic necrosis in rats on an alcoholic diet. J Pathol 152, 47—53.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Chanda S., Mangipudy, R.S., Warbritton, A., Bucci, T.J., and Mehendale, H.M. (1995). Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality. Hepatology 21, 477—86.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Chen J., Ishac, E.J., Dent, P., Kunos, G., and Gao, B. (1998). Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver. Biochem J 334, 669—76.[ISI][Medline] [Order article via Infotrieve]
  • Colell, A., Garcia-Ruiz, C., Miranda, M., Ardite, E., Mari, M., Morales, A., Kaplowitz, N., and Fernandez-Checa, J.C. (1998). Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 115, 1541—51.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Day, C.P., and James, O.F. (1998). Hepatic steatosis: innocent bystander or guilty party. Hepatology 27, 1463—6.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Deaciuc, I.V., D'Souza, N.B., Burikhanov, R., Lee, E.Y., Tarba, C.N., McClain, C.J., and de Villiers, W.J.S. (2002). Epidermal growth factors protects the liver against alcohol-induced injury and sensitization to bacterial lipopolysaccharide. Alcohol Clin Exp Res 26, 864—74.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Diehl, A.M. (1999). Effect of ethanol on tumor necrosis factor signaling during liver regeneration. Clin Biochem 32, 571—78.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Diehl, A.M. (2002a). Liver disease in alcohol abusers: Clinical perspective. Alcohol 27, 7—11.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Diehl, A.M. (2002b). Liver regeneration. Front Biosci. 7, e301—314.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Diehl, A.M., Yang, S.Q., Cote, P., and Wand, G.S. (1992). Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver. Hepatology 16, 1212—9.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Enomoto, N., Yamashita, S., Kono, H., Schemmer, P., Rivera, C.A., Enomoto, A. Nishiura, T., Nishimura, T., Brenner, D.A., and Thurman, R.G. (1999). Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells. Hepatology 29, 1680—9.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Essani, N.A., McGuire, G.M., Manning, A.M., and Jaeschke, H. (1996). Endotoxin-induced activation of the nuclear transcription factor kappa B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells and endothelial cells in vivo. J Immunol 156, 2956—63.[Abstract]
  • Everett, L., Galli, A., and Crabb, D. (2000). The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. Liver 20, 191—99.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Fausto, N., and Campbell, J.S. (2003). The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120, 117—30.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Fausto, N., Laird, A.D., and Webber, E.M. (1995). Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J 9, 1527—36.[Abstract]
  • Fausto, N. (2000). Liver Regeneration. J Hepatol 32, 19—31.[ISI][Medline] [Order article via Infotrieve]
  • Fischer, M., You, M., Matsumoto, M., and Crabb, D.W. (2003). Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J Biol Chem 278, 27997—28004.[Abstract/Free Full Text]
  • Galli, A., Pinaire, J., Fischer, M., Dorris, R., and Crabb, D. (2001). The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem 276, 68—75.[Abstract/Free Full Text]
  • Galum, E., Zeira, E., Pappo, O., Peters, M., and Rose-John, S. (2000). Liver regeneration induced by a designer human IL-6/sIL-6R fusion protein reverses severe hepatocellular injury. FASEB J 14, 1979—87.[Abstract/Free Full Text]
  • Gavrieli, Y., Sherman, Y., and Ben-Sasson, S.A. (1992). Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119, 493—501.[Abstract/Free Full Text]
  • Gouillon, Z.Q., Miyamoto, K., Donohue, T.M., Wan, Y.J., French, B.A., Nagao, Y., Fu, P., Reitz, R.C., Hagbjork, A., Yap, C., Yuan, Q.X., Ingelman-Sundberg, M., and French, F.W. (1999). Role of CYP2E1 in the pathogenesis of alcoholic liver disease: modifications by cAMP and ubiquitin-proteasome pathway. Front Biosci 4, A16—25.[Medline] [Order article via Infotrieve]
  • Greenwell, A., Foley, J.F., and Maronpot, R.R. (1991). An enhancement method for immunohistochemical staining of proliferating cell nuclear antigen in archival rodent tissues. Cancer Lett 59, 251—6.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Hilden, M., Christoffson, P., Juhl, E., and Dalgaard, J.B. (1977). Liver histology in a `normal' population-Examination of 503 consecutive fatal traffic casualties. Scan J Gastroenterol 12, 593—7.[ISI][Medline] [Order article via Infotrieve]
  • Koop, D.R. (1990). Inhibition of ethanol-inducible cytochrome P450IIE1 by 3-amino-1,2,4-triazole. Chem. Res. Toxicol 3, 377—83.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Koteish, A., Yang, S., Lin, H., Huang, J., and Diehl, A.M. (2002). Ethanol induces redox sensitive cell cycle inhibitors and inhibits liver regeneration after partial hepatectomy. Alcohol Clin Exp Res 26, 1710—8.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Leevy, C.M., and Chen, T. (1979). Ethanol inhibition of liver regeneration. Gastroenterology 77, 1151—3.[ISI][Medline] [Order article via Infotrieve]
  • Lieber, C.S. (1990). Alcohol metabolism and liver injury. Pharmacol Ther 46, 1—41.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Lieber, C.S. (2000). Alcohol: its metabolism and interaction with nutrients. Annu Rev Nutr 20, 395—430.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • MacSween, R.N., and Burt, A.D. (1986). Histological spectrum of alcoholic liver disease. Semin Liver Dis 6, 221—32.[ISI][Medline] [Order article via Infotrieve]
  • Maher, J.J. (2002). Alcoholic steatosis and steatohepatitis. Semin Gastrointest Dis 13, 31—9.[Medline] [Order article via Infotrieve]
  • McGehee, R.E. Jr., Ronis, M.J., and Badger, T.M. (1997). Regulation of the hepatic CYP 2E1 gene during chronic alcohol exposure: lack of an ethanol response element in the proximal 5'-flanking sequence. DNA Cell Biol 16, 725—36.[ISI][Medline] [Order article via Infotrieve]
  • McGregor, A.H., More, L.J., Simpson, K.J., and Harrison, D.J. (2003). Liver death and regeneration in paracetamol toxicity. Hum Exp Toxicol 22, 221— 27.[Abstract/Free Full Text]
  • Mehendale, H.M. (1995). Toxicodynamics of low level toxicant interactions of biological significance: inhibition of tissue repair. Toxicology 105, 251— 66.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Minuk, G.Y., Rockman, G.E., Gauthier, T., Markert, L., Gibson, J., and Benarroch, A. (1991). The effect of long-term, voluntary ethanol consumption on hepatic regeneration in rats. Can J Physiol Pharmacol 69, 341—5.[ISI][Medline] [Order article via Infotrieve]
  • Nanji, A. (2002). Alcoholic liver disease. In Hepatology, A Text Book of Liver Disease (D. Zakim, and T. D. Boyer, eds.), pp. 839—922. W. B. Saunders, Philadelphia.
  • Nanji, A.A., Jokelainen, K., Tipoe, G.L., Rahemtulla, A., Thomas, P., and Dannenberg, A.J. (2003). Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-{kappa}B-dependent genes. Am J Physiol Gastrointest Liver Physiol 284, G321—7.[Abstract/Free Full Text]
  • Nanji, A.A., Tsukamoto, H., and French, S.W. (1989). Relationship between fatty liver and subsequent development of necrosis, inflammation and fibrosis in experimental alcoholic liver disease. Exp Mol Pathol 51, 141—8.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • National Institute on Alcohol Abuse and Alcoholism. (2001). Alcohol Alert No. 51. NIAA, Bethesda, Md.
  • Oneta, C.M., Lieber, C.S., Li, J., Ruttimann, S., Schmid, B., Lattmann, J., Rosman, A.S., and Seitz, H.K. (2002). Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol 36, 47—52.[ISI][Medline] [Order article via Infotrieve]
  • Pennington, H.L., Hall, P.M., Wilce, P.A., and Worrall, S. (1997). Ethanol feeding enhances inflammatory cytokine expression in lipopolysaccharide-induced hepatitis. J Gastroenterol Hepatol 12, 305—13.[ISI][Medline] [Order article via Infotrieve]
  • Phillips, M., Kashef, E., and Hughes, R. (2002). Cellular mechanisms of liver regeneration and the effect of alcohol. In Ethanol and The Liver Mechanisms and Management (D. Sherman, V. Preedy, and R. R. Watson, eds.), pp. 319—42. Taylor and Francis, London and New York.
  • Ramaiah, S.K., Bucci, T.J., Warbritton, A., Soni, M.G., and Mehendale, H.M. (1998). Temporal changes in tissue repair permit survival of diet-restricted rats from an acute lethal dose of thioacetamide. Toxicol Sci 45, 233— 41.[Abstract/Free Full Text]
  • Roberts, B.J., Shoaf, S.E., and Song, B.J. (1995). Rapid changes in cytochrome P4502E1 (CYP2E1) activity and other P450 isozymes following ethanol withdrawal in rats. Biochem Pharmacol 49, 1665—73.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Saso, K., Moehren, G., Higashi, K., and Hoek, J.B. (1997). Differential inhibition of epidermal growth factor signaling pathways in rat hepatocytes by long-term ethanol treatment. Gastroenterology 112, 2073—88.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Shayiq, R.M., Roberts, D.W., Rothstein, K., Snawder, J.E., Benson, W., Ma, X., and Black, M. (1999). Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology 29, 451—63.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Soni, M.G., and Mehendale, H.M. (1998). Role of tissue repair in toxicologic interactions among hepatotoxic organics. Environ Health Perspect 106, 1307—17.[ISI][Medline] [Order article via Infotrieve]
  • Sorensen, T.I., Orholm, M., Bentsen, K.D., Hoybye, G., Eghoje, K., and Christoffersen, P. (1984). Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet 2, 241—4.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Taub, R. (1996). Liver regeneration 4: transcriptional control of liver regeneration. FASEB J 10, 413—27.[Abstract]
  • Teli, M.R., Day, C.P., Burt, A.D., Bennett, M.K., and James, O.F.W. (1995). Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 346, 987—90.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Underwood Ground, K.E. (1984). Prevalence of fatty liver in healthy male adults accidently killed. Aviat Space Environ Med 55, 59—61.[Medline] [Order article via Infotrieve]
  • Wands, J.R., Carter, E.A., Bucher, N.L., and Isselbacher, K.J. (1980). Effect of acute and chronic ethanol intoxication on hepatic regeneration. Adv Exp Med Biol 132, 663—70.[Medline] [Order article via Infotrieve]
  • Wang, T., Shankar, K., Ronis, M.J., and Mehendale, H.M. (2000). Potentiation of thioacetamide liver injury in diabetic rats is due to induced CYP2E1. J Pharmacol Exp Ther 294, 473—79.[Abstract/Free Full Text]
  • Yang, S.Q., Lin, H.Z., Lane, M.D., Clemens, M., and Diehl, A.M. (1997). Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci USA 94, 2557— 62.[Abstract/Free Full Text]
  • Yang, S.Q., Lin, H.Z., Yin, M., Albrecht, J.H., and Diehl, A.M. (1998). Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Physiol 275, G696—704.[ISI][Medline] [Order article via Infotrieve]
  • Zhang, B.H., and Farrell, G.C. (1999). Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-gamma1: relevance to impaired hepatocyte proliferation. Biochem Biophys Res Commun 257, 89—94.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Zhang, M., Gong, Y., Corbin, I., Mellon, A., Choy, P., Uhanova, J., and Minuk, G.Y. (2000). Light ethanol consumption enhances liver regeneration after partial hepatectomy in rats. Gastroenterology 119, 1333—9.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Zhang, M., Gong, Y.W., and Minuk, G.Y. (1998). The effects of ethanol and gamma aminobutyric acid alone and in combination on hepatic regenerative activity in the rat. J Hepatol 29, 638—41.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Zhang, M., Uhanova, J., Corbin, I., Bernstein, C., and Minuk, G.Y. (2003). Effects of daily, light and moderate-heavy ethanol exposure on extent of hepatic injury and recovery following toxin-induced acute hepatitis in rats. Dig Dis Sci 48, 926—31.[CrossRef][ISI][Medline] [Order article via Infotrieve]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
X. Kang, Z. Song, C. J. McClain, Y. J. Kang, and Z. Zhou
Zinc Supplementation Enhances Hepatic Regeneration by Preserving Hepatocyte Nuclear Factor-4{alpha} in Mice Subjected to Long-Term Ethanol Administration
Am. J. Pathol., April 1, 2008; 172(4): 916 - 925.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Apte, U. M.
Right arrow Articles by Ramaiah, S. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Apte, U. M.
Right arrow Articles by Ramaiah, S. K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?