Abstract |
Peroxisome proliferator-activated receptor-α (PPARα) mediates the diverse biological effects of peroxisome proliferator (PP) chemicals, including fatty acid catabolism, hepatomegaly, hepatocyte proliferation, and hepatocarcinogenesis in rodents. However, transgenic mice expressing a constitutively active PPARα in hepatocytes (VP16PPARα) do not develop hepatocellular carcinomas in spite of hepatocyte proliferation and hepatomegaly; this suggests that activation of genes in nonparenchymal cells may have a critical role in PP-induced carcinogenesis. VP16PPARα mice exhibited massive peroxisome proliferation and hepatomegaly as well as increased mortality upon Wy-14,643 treatment. Several genes involved in cell cycle or DNA damage repair, such as Chek1, Prkdc, Mcm, and Rad51, were significantly induced to a similar extent between wild-type and VP16PPARα mice after Wy-14,643 administration. This induction was completely abolished in Pparα-null mice, suggesting a PPARα-dependent pathway. These data revealed a DNA damage response signaling network as an early event upon PP treatment and provide novel putative mechanisms for PP-induced hepatocellular carcinoma.
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Authors | Aijuan Qu, Yatrik M Shah, Tsutomu Matsubara, Qian Yang, Frank J Gonzalez |
Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 118
Issue 2
Pg. 404-10
(Dec 2010)
ISSN: 1096-0929 [Electronic] United States |
PMID | 20813756
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Chemical References |
- PPAR alpha
- Peroxisome Proliferators
- Pyrimidines
- pirinixic acid
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Topics |
- Animals
- Cell Cycle
(genetics)
- Cell Proliferation
(drug effects)
- DNA Damage
- DNA Repair
(genetics)
- Gene Expression
(drug effects)
- Gene Expression Profiling
- Hepatocytes
(drug effects, metabolism, pathology)
- Hepatomegaly
(chemically induced, genetics, pathology)
- Kupffer Cells
(drug effects, metabolism, pathology)
- Liver
(drug effects, metabolism, pathology)
- Longevity
(drug effects)
- Male
- Mice
- Mice, Knockout
- Organ Size
(drug effects)
- PPAR alpha
(deficiency, genetics, metabolism)
- Peroxisome Proliferators
(pharmacology)
- Pyrimidines
(pharmacology)
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