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1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
2 Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim, Norway
3 The Linnaeus Center for Bioinformatics, Uppsala University, Uppsala, Sweden
* To whom correspondence should be addressed. E-mail: fekadu.yadetie{at}medisin.ntnu.no.
Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor alpha (PPAR
), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body weight per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPAR agonist responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate dosed rats, and some of these are potential targets of PPAR. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.
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