A chemical switch regulates fibrate specificity for peroxisome proliferator-activated receptor alpha (PPARalpha ) versus liver X receptor.
Fenofibrate is clinically successful in treating hypertriglyceridemia and mixed hyperlipidemia presumably through peroxisome proliferator-activated receptor alpha (PPARalpha)-dependent induction of genes that control fatty acid beta-oxidation. Lipid homeostasis and cholesterol metabolism also are regulated by the nuclear oxysterol receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta). Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs. Likewise, ester forms, but not carboxylic acid forms, of other members of the fibrate class of molecules antagonize the LXRs. The fibrate esters display greater affinity for LXRs than the corresponding fibric acids have for PPARalpha. Thus, these two nuclear receptors display a degree of conservation in their recognition of ligands; yet, the acid/ester moiety acts as a chemical switch that determines PPARalpha versus LXR specificity. Consistent with its LXR antagonistic activity, fenofibrate potently represses LXR agonist-induced transcription of hepatic lipogenic genes. Surprisingly, fenofibrate does not repress LXR-induced transcription of various ATP-binding cassette transporters either in liver or in macrophages, suggesting that fenofibrate manifests variable biocharacter in the context of differing gene promoters. These findings provide not only an unexpected mechanism by which fenofibrate inhibits lipogenesis but also the basis for examination of the pharmacology of an LXR ligand in humans.
Thomas
Jeffrey
J
Department of Cardiovascular Research, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
Bramlett
Kelli S
KS
Montrose
Chahrzad
C
Foxworthy
Patricia
P
Eacho
Patrick I
PI
McCann
Denis
D
Cao
Guoqing
G
Kiefer
Anton
A
McCowan
Jeff
J
Yu
Kuo-Long
KL
Grese
Timothy
T
Chin
William W
WW
Burris
Thomas P
TP
Michael
Laura F
LF
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000960:Hypolipidemic Agents / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D008956:Models, Chemical; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012588:Scintillation Counting; D013449:Sulfonamides; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000924:Anticholesteremic Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011345:Fenofibrate; D006845:Hydrocarbons, Fluorinated; D000960:Hypolipidemic Agents; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014157:Transcription Factors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C081168:abcA protein, Aeromonas salmonicida