Carcinogenesis Advance Access originally published online on September 24, 2004
Carcinogenesis 2005 26(1):219-227; doi:10.1093/carcin/bgh285
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
ARTICLE |
Role of peroxisome proliferator-activated receptor-
(PPAR) in bezafibrate-induced hepatocarcinogenesis and cholestasis
1 Department of Veterinary Science and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA, 2 Department of Environmental Sciences and Engineering, The University of North Carolina, Chapel Hill, NC 27599, USA, 3 Infectious Disease Pathogenesis Section, Comparative Medicine Branch and SoBran, Inc., National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA and 4 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
5 To whom correspondence should be addressed Email: jmp21{at}psu.edu
Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-
(PPAR) is required to mediate alterations in PPAR target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPAR agonist, Wy-14,643. Interestingly, administration of the less specific PPAR agonist, bezafibrate, leads to a modest induction of PPAR target genes in the absence of PPAR expression. In these studies, the role of PPAR in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPAR-null (–/–) mice. The average liver weight was significantly higher in (+/+) and (–/–) mice fed bezafibrate than controls, but this effect was considerably less in (–/–) mice as compared with similarly treated (+/+) mice. Increased levels of mRNA encoding cell cycle regulatory proteins and DNA repair enzymes were found in (+/+) mice fed bezafibrate, and this effect was not found in (–/–) mice. In mice fed bezafibrate for 1 year, preneoplastic foci, adenomas and a hepatocellular carcinoma were found in (+/+) mice, while only a single microscopic adenoma was found in one (–/–) mouse. This effect was observed in both Sv/129 and C57BL/6N strains of mice, although only preneoplastic foci were observed in the latter strain. Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (–/–) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor. Results from these studies demonstrate that the PPAR is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPAR protects against potential cholestasis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. E. Foreman, S.-C. Chang, D. J. Ehresman, J. L. Butenhoff, C. R. Anderson, P. S. Palkar, B.-H. Kang, F. J. Gonzalez, and J. M. Peters Differential Hepatic Effects of Perfluorobutyrate Mediated by Mouse and Human PPAR-{alpha} Toxicol. Sci., July 1, 2009; 110(1): 204 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Gyamfi and Y.-J. Y. Wan Mechanisms of Resistance of Hepatocyte Retinoid X Receptor {alpha}-Null Mice to WY-14,643-induced Hepatocyte Proliferation and Cholestasis J. Biol. Chem., April 3, 2009; 284(14): 9321 - 9330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nakajima, N. Tanaka, H. Kanbe, A. Hara, Y. Kamijo, X. Zhang, F. J. Gonzalez, and T. Aoyama Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor {alpha}-Independent Mechanism Mol. Pharmacol., April 1, 2009; 75(4): 782 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gopinathan, D. B. Hannon, J. M. Peters, and J. P. Vanden Heuvel Regulation of Peroxisome Proliferator-Activated Receptor-{alpha} by MDM2 Toxicol. Sci., March 1, 2009; 108(1): 48 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Faiola, J. G. Falls, R. A. Peterson, N. R. Bordelon, T. A. Brodie, C. A. Cummings, E. H. Romach, and R. T. Miller PPAR alpha, more than PPAR delta, Mediates the Hepatic and Skeletal Muscle Alterations Induced by the PPAR Agonist GW0742 Toxicol. Sci., October 1, 2008; 105(2): 384 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Theve, Y. Feng, K. Taghizadeh, K. S. Cormier, D. R. Bell, J. G. Fox, and A. B. Rogers Sex Hormone Influence on Hepatitis in Young Male A/JCr Mice Infected with Helicobacter hepaticus Infect. Immun., September 1, 2008; 76(9): 4071 - 4078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Rosen, J. S. Lee, H. Ren, B. Vallanat, J. Liu, M. P. Waalkes, B. D. Abbott, C. Lau, and J. C. Corton Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPAR{alpha} and CAR Toxicol. Sci., May 1, 2008; 103(1): 46 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Peters Mechanistic Evaluation of PPAR{alpha}-Mediated Hepatocarcinogenesis: Are We There Yet? Toxicol. Sci., January 1, 2008; 101(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 Q. Yang, S. Ito, and F. J. Gonzalez Hepatocyte-restricted constitutive activation of PPAR{alpha} induces hepatoproliferation but not hepatocarcinogenesis Carcinogenesis, June 1, 2007; 28(6): 1171 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]
|
|