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Carcinogenesis Advance Access originally published online on February 28, 2007
Carcinogenesis 2007 28(6):1171-1177; doi:10.1093/carcin/bgm046
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Hepatocyte-restricted constitutive activation of PPAR{alpha} induces hepatoproliferation but not hepatocarcinogenesis

Qian Yang, Shinji Ito and Frank J. Gonzalez*

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +301 496 9067; Fax: +301 496 8419; Email: fjgonz{at}helix.nih.gov

Peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) 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{alpha} only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPAR{alpha} 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{alpha} 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 non-parenchymal cells (NPCs). Thus, activation of hepatic NPCs and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.

Abbreviations: ACOX, acyl-CoA oxidase; BrdU, 5-bromo-2'-deoxyuridine; CDK, cyclin-dependent kinase; dox, doxycycline; LAP, liver-enriched activator protein; NPC, non-parenchymal cell; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PP, peroxisome proliferator chemical; PPAR, peroxisome proliferator-activated receptor; tTA, tetracycline-controlled transactivator; (Wt), wild-type

Received November 29, 2006; revised February 16, 2007; accepted February 20, 2007.


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