Altered expression of nuclear receptors affects the expression of metabolic enzymes and transporters in a rat model of cholestasis.
Hepatic metabolism is altered in some clinical conditions owing to the changes in the expression of metabolic enzymes and transporters. Therefore, we think that investigating the altered expression of metabolic enzymes and transporters is of particular significance to studies on drug disposition in some clinical conditions. We also believe that a simultaneous in vivo investigation of all factors affecting nuclear receptors and regulated genes is important to understand the relationship between nuclear receptors and their target genes. In this study, we induced cholestasis in rats by bile duct ligation (BDL), and investigated the changes in the mRNA expression of metabolic enzymes, transporters, and nuclear receptors and the protein levels of nuclear receptors in the nucleus by reverse transcriptase-polymerase chain reaction and Western blotting. In the liver of the rats subjected to BDL, the mRNA expression levels of cytochrome P450, conjugation enzymes, and transporters were concomitantly altered. The altered mRNA and protein levels of constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor alpha (PPARalpha) in the nucleus were consistent with the changes in the plasma concentrations of total and conjugated bilirubin and fatty acid, respectively. The mRNA expression of CAR and PPARalpha was linearly associated with the expression of the corresponding target genes. These results suggested that the increase in the levels of bilirubin and fatty acid on the BDL groups altered the mRNA and protein levels of CAR and PPARalpha, respectively in the nucleus, and this in turn altered the mRNA expression of metabolic enzymes and transporters as a hepatoprotective mechanism.
Hasegawa
Yoshitaka
Y
Laboratory of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Kishimoto
Shuichi
S
Takahashi
Hirokazu
H
Inotsume
Nobuo
N
Takeuchi
Yoshikazu
Y
Fukushima
Shoji
S
D000818:Animals; D001652:Bile Ducts; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002779:Cholestasis / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000097:blood; D015870:Gene Expression; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000090702:Constitutive Androstane Receptor; D004798:Enzymes; D005227:Fatty Acids; D026901:Membrane Transport Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D001663:Bilirubin