Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver.
Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and enhance the transcription of several genes in liver. We report here that synthetic PPARalpha ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adenoviral-enhanced green fluorescent protein-CAR expression demonstrated that PPARalpha synthetic ligands drive CAR into the hepatocyte nucleus in a PPARalpha- and PPARbeta-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPARalpha ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPARalpha ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPARalpha ligands not only serve as PPARalpha agonists but possibly act as CAR antagonists.
Guo
Dongsheng
D
Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008, USA.
Sarkar
Joy
J
Suino-Powell
Kelly
K
Xu
Yong
Y
Matsumoto
Kojiro
K
Jia
Yuzhi
Y
Yu
Songtao
S
Khare
Sonal
S
Haldar
Kasturi
K
Rao
M Sambasiva
MS
Foreman
Jennifer E
JE
Monga
Satdarshan P S
SP
Peters
Jeffrey M
JM
Xu
H Eric
HE
Reddy
Janardan K
JK
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000737:Androstenols / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000737:Androstenols; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D047493:PPAR alpha; D048068:PPAR-beta; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2