Yadetie Fekadu, Laegreid Astrid, Bakke Ingunn, Kusnierczyk Waclaw, Komorowski Jan, Waldum Helge L, Sandvik Arne K
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
Physiol Genomics. 2003 Sep 29;15(1):9-19. doi: 10.1152/physiolgenomics.00064.2003.
Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-alpha (PPARalpha), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt 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 PPARalpha 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 PPARalpha. 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.
贝特类降血脂药物如环丙贝特可激活过氧化物酶体增殖物激活受体α（PPARα），该受体参与啮齿动物的脂质代谢和肝细胞增殖等过程。我们使用cDNA微阵列研究了环丙贝特（每天50 mg/kg体重，持续60天）对大鼠肝脏基因表达的影响。选择60天的给药期以阐明该物质的代谢和增殖作用，同时避免长期刺激期间出现的肝脏致癌作用带来的混淆效应。环丙贝特改变了许多基因的表达，包括先前已知的参与脂质代谢和炎症反应等过程的PPARα激动剂反应性基因。此外，许多参与糖代谢、转录、信号转导、细胞增殖和应激反应的新候选基因在给予环丙贝特的大鼠中似乎受到不同程度的调节。环丙贝特还导致肝脏重量和肝细胞增殖显著增加。通过对选定基因的Northern印迹分析证实了cDNA微阵列的结果。因此，本研究鉴定了许多在给予环丙贝特的大鼠中似乎受到不同程度调节的基因，其中一些是PPARα的潜在靶点。这些候选基因的功能多样性表明，它们中的大多数可能是环丙贝特在啮齿动物肝脏中影响的许多过程的间接结果而受到不同程度的调节。尽管在解释全基因组表达数据时应谨慎，但本研究中鉴定的基因提供了进一步研究的候选对象，可能会为过氧化物酶体增殖剂的作用机制提供新的见解。
