PPARalpha-dependent activation of cell cycle control and DNA repair genes in hepatic nonparenchymal cells.

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.

• 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)

Chemical References

• PPAR alpha
• Peroxisome Proliferators
• Pyrimidines
• pirinixic acid

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)