|Voss, Kenneth - Ken|
Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2003
Publication Date: 3/1/2003
Citation: Toxicologist. 2003. v.77. Abstract. p.252. Interpretive Summary: abstract only
Technical Abstract: A number of mouse mutants that exhibit decreased levels of reactive oxygen species (ROS) and increases in longevity carry mutations in growth hormone signaling genes. In gene expression profiling experiments we observed in the livers of Snell dwarf mice an increase in the expression of genes under control of the nuclear receptor peroxisome proliferator (PP)-activated receptor alpha (PPAR) as well as PPAR itself. PPAR mediates the carcinogenic effects of PP and is a known or experimental therapeutic target for PP drugs in diseases associated with aging in which oxidative stress plays a major role. Transcript profiling experiments in wild-type mice treated with a PPAR agonist, revealed coordinated increases in the expression of members of heat shock protein (HSP) and anti-oxidant gene families. HSPs are required for the correct folding of nacent polypeptides and repair of misfolded proteins after damage from chemicals that induce ROS. We examined the extent of the overlap in regulated genes between a PP and a classical heat stress by exposing wild- type or PPAR-null mice to a 25 or 42 degree C heat stress for 40 min. Transcript profile experiments using Affymetrix chips containing -9,000 mouse genes were used to assess gene expression in the livers of the mice. We found that PPAR-null mice 1) exhibit defects in HSP gene product induction after heat shock or PP treatment, 2) are more sensitive to hepatocellular damage from treatments that increase oxidative stress, and 3) show decreased longevity. Our results are consistent with the hypothesis that PPAR alpha controls stress resistance and longevity through coordinated regulation of genes that mediate responses to ROS including members of the HSP gene family.