Carcinogenesis Advance Access published online on February 28, 2007
Carcinogenesis, doi:10.1093/carcin/bgm046
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hepatocyte-restricted constitutive activation of PPAR
induces hepatoproliferation but not hepatocarcinogenesis
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
* Correspondence: Frank J. Gonzalez, Building 37, Room 3106, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-9067. Fax: (301) 496-8419. E-mail: fjgonz{at}helix.nih.gov
Peroxisome proliferator-activated receptor 
(PPAR) is responsible for peroxisome proliferator-induced pleiotropic responses, including the development of hepatocellular carcinoma in rodents. However, it remains to be determined whether activation of PPAR only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPAR specifically to hepatocytes. The transgenic mice exhibited various responses that mimic wild-type mice treated with peroxisome proliferators, including significantly decreased serum fatty acids and marked induction of PPAR target genes encoding fatty acid oxidation enzymes, suggesting that the transgene functions in the same manner as peroxisome proliferators to regulate fatty acid metabolism. However, the transgenic mice did not develop hepatocellular carcinomas, even though they exhibited peroxisome proliferation and hepatocyte proliferation, indicating that these events are not sufficient to induce liver cancer. In contrast to the transgenic mice, peroxisome proliferators activate proliferation of hepatic nonparenchymal cells. Thus, activation of hepatic nonparechymal cells and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.
Key Words: VP16PPAR • LAP • carcinogenesis • hepatocytes • tet-off • doxycycline
Received November 29, 2006; revised February 16, 2007; accepted February 20, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Cederberg, J. Henriksson, and M.-L. Binderup DNA damage detected by the alkaline comet assay in the liver of mice after oral administration of tetrachloroethylene Mutagenesis, November 5, 2009; (2009) gep051v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Bjork and K. B. Wallace Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid-Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures Toxicol. Sci., September 1, 2009; 111(1): 89 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Liu, A. D. Patterson, Z. Yang, X. Zhang, W. Liu, F. Qiu, H. Sun, K. W. Krausz, J. R. Idle, F. J. Gonzalez, et al. Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics Drug Metab. Dispos., June 1, 2009; 37(6): 1157 - 1163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Clark, T. P. Ryan, G. H. Searfoss, M. A. Davis, and S. B. Hooser Chronic Microcystin Exposure Induces Hepatocyte Proliferation with Increased Expression of Mitotic and Cyclin-associated Genes in P53-deficient Mice Toxicol Pathol, February 1, 2008; 36(2): 190 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yang, T. Nagano, Y. Shah, C. Cheung, S. Ito, and F. J. Gonzalez The PPAR{alpha}-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPAR{alpha} Toxicol. Sci., January 1, 2008; 101(1): 132 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez Peroxisome Proliferator-Activated Receptor {alpha} Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation Mol. Cell. Biol., June 15, 2007; 27(12): 4238 - 4247. [Abstract] [Full Text] [PDF]
|
|