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.
Department of Anatomy and Cell Biology, University of Alberta, Edmonton, Canada.
C J
CJ
Winrow
S L
SL
Marcus
K S
KS
Miyata
B
B
Zhang
J P
JP
Capone
R A
RA
Rachubinski
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