Microarray analysis of gene expression changes in mouse liver induced by peroxisome proliferator- activated receptor alpha agonists.
We used a microarray technique to investigate changes of gene expression in liver induced by two peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, a strong PPARalpha agonist, Wy-14,643, and a marketed fibrate drug, fenofibrate. The purposes of this work are: 1) to examine whether or not gene expression is altered in different ways by these two PPARalpha agonists and 2) to find genes whose expression has not been previously reported to be affected by PPARalpha agonists. Mice were treated orally with 100 mg/kg fenofibrate, or 30 mg/kg or 100 mg/kg Wy-14,643, and the liver was collected on Day 2 or 3. mRNA was extraction from liver, and subjected to microarray analysis. Previously reported induction or reduction of gene expression, e.g. genes involved in beta-oxidation and lipid metabolism, was confirmed in our study. Scatter plot analysis indicated that the changes of gene expression pattern induced by fenofibrate and Wy-14,643 were almost identical. However, expression levels of metallothionein 1 and 2 mRNAs were different: no change of hepatic metallothionein 1 and 2 mRNA expression was induced by 100 mg/kg fenofibrate on Day 2 or 3, while 30 mg/kg Wy-14,643 administration increased expression of both genes by 1.8-fold on Day 3. In addition to previously reported gene expression changes by PPARalpha agonists, we found expression changes of other genes, including cis-retinol/3alpha-hydroxysterol short chain dehydrogenase, vanin-1, RecA-like protein, and serum amyloid A (SAA) 2. Among them, the change of SAA2 mRNA level was noteworthy; it showed a decrease to as little as one-seventh. Seven-day fenofibrate pre-treatment of mice completely inhibited the acute-phase elevation of plasma SAA concentration triggered by acetaminophen challenge. This finding suggests that fenofibrate treatment may reduce plasma SAA concentration in patients with secondary amyloidosis.
Yamazaki
Kazuto
K
Tsukuba Research Laboratories, Eisai Company, Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan. k5-yamazaki@hhc.eisai.co.jp
Kuromitsu
Junro
J
Tanaka
Isao
I
D000210:Acute-Phase Reaction / Q000097:blood; D000818:Animals; D015536:Down-Regulation; D011345:Fenofibrate / Q000494:pharmacology*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*
D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; D014157:Transcription Factors; C006253:pirinixic acid; D008668:Metallothionein; D011345:Fenofibrate