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

Toxicol Sci. 2010 Dec;118(2):404-10. doi: 10.1093/toxsci/kfq259. Epub 2010 Sep 2.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Cycle / genetics*
  • Cell Proliferation / drug effects
  • DNA Damage
  • DNA Repair / genetics*
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Hepatomegaly / chemically induced
  • Hepatomegaly / genetics
  • Hepatomegaly / pathology
  • Kupffer Cells / drug effects
  • Kupffer Cells / metabolism*
  • Kupffer Cells / pathology
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Longevity / drug effects
  • Male
  • Mice
  • Mice, Knockout
  • Organ Size / drug effects
  • PPAR alpha / deficiency
  • PPAR alpha / genetics*
  • PPAR alpha / metabolism
  • Peroxisome Proliferators / pharmacology
  • Pyrimidines / pharmacology


  • PPAR alpha
  • Peroxisome Proliferators
  • Pyrimidines
  • pirinixic acid