Evidence for direct binding of fatty acids and eicosanoids to human peroxisome proliferators-activated receptor alpha.
The alpha isoform of peroxisome proliferators-activated receptor (PPAR) is activated by fatty acids, their metabolites, and the fibrate class of lipid-lowering agents. To test the ability of these activators to directly bind the ligand-binding domain of human PPARalpha, we performed a competitive binding assay using radiolabeled [(3)H]KRP-297, a known ligand for human PPARalpha. Long-chain fatty acids and eicosanoids were even more potent ligands for human PPARalpha than the hitherto most potent PPARalpha ligand WY-14,643. Moreover, these natural ligands avidly activated this receptor in a transient transcriptional assay. This study provides the direct evidence that human PPARalpha is activated through the direct binding of fatty acids and eicosanoids, as well as of a fibrate, to its ligand-binding domain.
Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
K
K
Murakami
T
T
Ide
M
M
Suzuki
T
T
Mochizuki
T
T
Kadowaki
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D015777:Eicosanoids / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism; D053778:Thiazolidines; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D015777:Eicosanoids; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008024:Ligands; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D053778:Thiazolidines; D014157:Transcription Factors; C116017:5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide; C047628:8-hydroxyeicosatetraenoic acid; C006253:pirinixic acid