This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohmura, T. Articles by Shinozuka, H. Search for Related Content PubMed PubMed Citation Articles by Ohmura, T. Articles by Shinozuka, H.

American Journal of Pathology, Vol 148, 815-824, Copyright © 1996 by American Society for Investigative Pathology

REGULAR ARTICLES

Hepatocyte proliferation induced by a single dose of a peroxisome proliferator

T Ohmura, GM Ledda-Columbano, R Piga, A Columbano, J Glemba, SL Katyal, J Locker and H Shinozuka
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.

In compensatory hyperplasia after partial hepatectomy or liver cell injury, hepatocyte proliferation is triggered by coordinated actions of growth factor such as hepatocyte growth factor and transforming growth factor-alpha and -beta. Initiation of hepatocyte DNA synthesis is preceded by the activation of the set of early growth response genes mediated by enhanced nuclear factor-kappa B binding to DNA. Using an experimental model to induce hepatocyte DNA synthesis in vivo by a single dose of a peroxisome proliferator, which does not induce liver cell necrosis (direct hyperplasia), we investigated whether peroxisome proliferator-induced hepatocyte proliferation involved an induction of known growth factors, an activation of early growth response genes, and nuclear factor-kappa B. A single intragastric administration of 250 mg/kg BR931 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta- hydroxyethyl) acetamide) to male wistar rats induced a wave of hepatocyte DNA synthesis starting after 12 hours and peaking at approximately 24 to 36 hours. The response was dose dependent. The treatment also induced the expression of the mRNA for the peroxisomal bifunctional enzyme, one of the peroxisome-related fatty acid beta- oxidation enzymes. Pretreatment of rats with dexamethasone (2 mg/kg) inhibited both hepatocyte DNA synthesis and the induction of the peroxisomal bifunctional enzyme gene. Northern blot analyses of liver RNA during a period preceding the onset of DNA synthesis revealed no induction of hepatocyte growth factor, transforming growth factor- alpha, or tumor necrosis factor-alpha mRNAs. No induction of early growth response genes, liver regeneration factor-1, or c-myc was detected. Furthermore, gel mobility shift assays showed no enhanced nuclear factor-kappa B binding to its DNA consensus sequence after BR931 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment. The results suggest that peroxisome-proliferator-induced hepatocyte proliferation may be triggered by signal transduction pathways different from those after partial hepatectomy and that the binding of peroxisome proliferators to their nuclear receptors may play a role in stimulation of DNA synthesis and peroxisome proliferation.

This article has been cited by other articles:

				C. G. Woods, A. M. Burns, B. U. Bradford, P. K. Ross, O. Kosyk, J. A. Swenberg, M. L. Cunningham, and I. Rusyn WY-14,643 Induced Cell Proliferation and Oxidative Stress in Mouse Liver are Independent of NADPH Oxidase Toxicol. Sci., August 1, 2007; 98(2): 366 - 374. [Abstract] [Full Text] [PDF]

				G. Fava, Y. Ueno, S. Glaser, H. Francis, S. DeMorrow, L. Marucci, M. Marzioni, A. Benedetti, J. Venter, B. Vaculin, et al. Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca2+-dependent downregulation of SRC/ERK1/2 Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1467 - C1475. [Abstract] [Full Text] [PDF]

				R. A. Canuto, G. Muzio, M. Maggiora, A. Trombetta, G. Martinasso, R. Autelli, P. Costelli, G. Bonelli, and F. M. Baccino Apoptosis induced by clofibrate in Yoshida AH-130 hepatoma cells: role of HMG-CoA reductase J. Lipid Res., January 1, 2003; 44(1): 56 - 64. [Abstract] [Full Text] [PDF]

				S. P. Anderson, C. S. Dunn, R. C. Cattley, and J.C. Corton Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF{alpha} signaling Carcinogenesis, November 1, 2001; 22(11): 1843 - 1851. [Abstract] [Full Text] [PDF]

				G. M. Ledda-Columbano, M. Pibiri, R. Loi, A. Perra, H. Shinozuka, and A. Columbano Early Increase in Cyclin-D1 Expression and Accelerated Entry of Mouse Hepatocytes into S Phase after Administration of the Mitogen 1,4-Bis[2-(3,5-Dichloropyridyloxy)] Benzene Am. J. Pathol., January 1, 2000; 156(1): 91 - 97. [Abstract] [Full Text] [PDF]

				G.M. Ledda-Columbano, A. Perra, R. Piga, M. Pibiri, R. Loi, H. Shinozuka, and A. Columbano Cell proliferation induced by 3,3',5-triiodo-L-thyronine is associated with a reduction in the number of preneoplastic hepatic lesions Carcinogenesis, December 1, 1999; 20(12): 2299 - 2304. [Abstract] [Full Text] [PDF]