Transactivation of the peroxisome proliferator-activated receptor is differentially modulated by hepatocyte nuclear factor-4.
Peroxisome proliferator-activated receptors (PPARs) stimulate the expression of several genes involved in lipid metabolism by binding to specific cis-acting peroxisome proliferator-responsive elements (PPREs) via cooper-ativity with retinoid X receptors. We demonstrate here that hepatocyte nuclear factor-4 (HNF-4), another member of the nuclear hormone receptor superfamily, bound with differing affinities to the PPREs from the genes encoding rat acyl-CoA oxidase and hydratase-dehydrogenase, the first two enzymes of the peroxisomal beta-oxidation pathway. In cotransfection assays, HNF-4 repressed rat PPAR-dependent activation of a reporter gene linked to the acyl-CoA oxidase PPRE, either in the absence or presence of the peroxisome proliferator, Wy-14,643. Rat PPAR-dependent activation of a reporter gene linked to the hydratase-dehydrogenase PPRE was less efficiently repressed by HNF-4 in the absence of Wy-14,643 than was activation from the acyl-CoA oxidase PPRE. However, in the presence of Wy-14,643, HNF-4 functioned cooperatively with PPAR to significantly enhanced induction from the hydratase-dehydrogenase PPRE. These results suggest that the genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway are subject to differential regulation by the interplay of multiple members of the steroid/nuclear hormone receptor superfamily, mitigated in part by the structures of the PPREs and by the presence of activators of PPARs.
Winrow
C J
CJ
Department of Anatomy and Cell Biology, University of Alberta, Edmonton, Canada.
Marcus
S L
SL
Miyata
K S
KS
Zhang
B
B
Capone
J P
JP
Rachubinski
R A
RA
D042962:Acyl-CoA Oxidase; D000818:Animals; D001483:Base Sequence; D015342:DNA Probes; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D008830:Microbodies / Q000187:drug effects; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D010750:Phosphoproteins; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
D015342:DNA Probes; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase