Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor alpha agonists.
BACKGROUND
Fibrates are a unique hypolipidemic drugs that lower plasma triglyceride and cholesterol levels through their action as peroxisome proliferator-activated receptor alpha (PPARalpha) agonists. The activation of PPARalpha leads to a cascade of events that result in the pharmacological (hypolipidemic) and adverse (carcinogenic) effects in rodent liver.


RESULTS
To understand the molecular mechanisms responsible for the pleiotropic effects of PPARalpha agonists, we treated mouse primary hepatocytes with three PPARalpha agonists (bezafibrate, fenofibrate, and WY-14,643) at multiple concentrations (0, 10, 30, and 100 microM) for 24 hours. When primary hepatocytes were exposed to these agents, transactivation of PPARalpha was elevated as measured by luciferase assay. Global gene expression profiles in response to PPARalpha agonists were obtained by microarray analysis. Among differentially expressed genes (DEGs), there were 4, 8, and 21 genes commonly regulated by bezafibrate, fenofibrate, and WY-14,643 treatments across 3 doses, respectively, in a dose-dependent manner. Treatments with 100 muM of bezafibrate, fenofibrate, and WY-14,643 resulted in 151, 149, and 145 genes altered, respectively. Among them, 121 genes were commonly regulated by at least two drugs. Many genes are involved in fatty acid metabolism including oxidative reaction. Some of the gene changes were associated with production of reactive oxygen species, cell proliferation of peroxisomes, and hepatic disorders. In addition, 11 genes related to the development of liver cancer were observed.


CONCLUSIONS
Our results suggest that treatment of PPARalpha agonists results in the production of oxidative stress and increased peroxisome proliferation, thus providing a better understanding of mechanisms underlying PPARalpha agonist-induced hepatic disorders and hepatocarcinomas.
Guo
Lei
L
Division of Systems Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. lei.guo@fda.hhs.gov
Fang
Hong
H
Collins
Jim
J
Fan
Xiao-hui
XH
Dial
Stacey
S
Wong
Alex
A
Mehta
Kshama
K
Blann
Ernice
E
Shi
Leming
L
Tong
Weida
W
Dragan
Yvonne P
YP
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology
D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D011345:Fenofibrate; D001629:Bezafibrate