Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.
Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150 microM concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily.
Göttlicher
M
M
Department of Medical Nutrition, Karolinska Institute, Huddinge, Sweden.
Widmark
E
E
Li
Q
Q
Gustafsson
J A
JA
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001483:Base Sequence; D016466:CHO Cells; D002678:Chimera; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology*; D006224:Cricetinae; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010920:Placenta / Q000201:enzymology; D016133:Polymerase Chain Reaction / Q000379:methods; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D000924:Anticholesteremic Agents; D005230:Fatty Acids, Nonesterified; D005231:Fatty Acids, Unsaturated; D009838:Oligodeoxyribonucleotides; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D003687:Dehydroepiandrosterone; D003907:Dexamethasone; C006253:pirinixic acid; D004247:DNA; D002784:Cholesterol; D000469:Alkaline Phosphatase; D002994:Clofibrate