Journal Article

Hepatocyte-restricted constitutive activation of PPARα induces hepatoproliferation but not hepatocarcinogenesis

Qian Yang, Shinji Ito and Frank J. Gonzalez

in Carcinogenesis

Volume 28, issue 6, pages 1171-1177
Published in print June 2007 | ISSN: 0143-3334
Published online February 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm046
Hepatocyte-restricted constitutive activation of PPARα induces hepatoproliferation but not hepatocarcinogenesis

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Peroxisome proliferator-activated receptor α (PPARα) 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 PPARα only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPARα 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 PPARα 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.

Journal Article.  5342 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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