The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes.
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARalpha in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARalpha-null mice. Primary hepatocytes from wild-type but not PPARalpha-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARalpha-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARalpha, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARalpha-null mice. Of the 815 genes regulated by WY in wild-type mice (p < or = 0.001; > or =1.5-fold or < or =-1.5-fold), only two genes were regulated similarly by WY in PPARalpha-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARalpha controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.
Anderson
Steven P
SP
Investigative Toxicology and Pathology Group, Safety Assessment, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
Howroyd
Paul
P
Liu
Jie
J
Qian
Xun
X
Bahnemann
Rainer
R
Swanson
Cynthia
C
Kwak
Mi-Kyoung
MK
Kensler
Thomas W
TW
Corton
J Christopher
JC
D000818:Animals; D001483:Base Sequence; D002104:Cadmium / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D004247:DNA / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists*; D010269:Paraquat / Q000633:toxicity; D020543:Proteome / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D047493:PPAR alpha; D020543:Proteome; D011743:Pyrimidines; D002104:Cadmium; C006253:pirinixic acid; D004247:DNA; D002251:Carbon Tetrachloride; D010269:Paraquat