Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells.
The liver X receptors (LXRalpha and LXRbeta), ligand-activated transcription factors, belong to the superfamily of nuclear hormone receptors and have been shown to play a major role in atherosclerosis by modulating cholesterol and triglyceride metabolism. In this report, we describe a novel LXR target, the adipocyte fatty acid binding protein (aP2), which plays an important role in fatty acid metabolism, adipocyte differentiation and atherosclerosis. While LXR agonists induce aP2 mRNA expression in human monocytes (THP-1 cells) and macrophages in a time- and concentration-dependent manner, they have no effect on aP2 expression in human adipocytes. The increase in aP2 mRNA level was additive when THP-1 cells were treated with LXR and PPARgamma agonists. Also, an RXR agonist induced aP2 expression in these cells. While no additive effect was observed with LXR and RXR agonists, additive effects were observed with RXR and PPARgamma agonists. GW9662, a potent PPARgamma antagonist, inhibited PPARgamma-induced aP2 expression without affecting LXR-mediated aP2 expression indicating the induction is mediated directly through LXR activation. Analysis of human aP2 promoter revealed a potential LXR response element (LXRE). Gel shift data showed that the LXRalpha/RXRalpha heterodimer bound to the LXRE motif in aP2 promoter in vitro in a sequence-specific manner. Deletion and mutation analyses of the proximal aP2 promoter confirm that this is a functional LXRE. These data indicate for the first time that human macrophage aP2 promoter is a direct target for the regulation by LXR/RXR heterodimers.
Liu
Qiang-Yuan
QY
Department of Cardiovascular and Metabolic Research, Wyeth Research, N-2275, 500 Arcola Rd., Collegeville, PA 19426, USA.
Quinet
Elaine
E
Nambi
Ponnal
P
D024506:5' Flanking Region / Q000235:genetics; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000077556:Alitretinoin; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism*; D019281:Dimerization; D004357:Drug Synergism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000819:agonists; D011485:Protein Binding / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D017384:Sequence Deletion; D013449:Sulfonamides / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000077556:Alitretinoin; D004268:DNA-Binding Proteins; D050556:Fatty Acid-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D013449:Sulfonamides; D045162:Thiazolidinediones; D014212:Tretinoin; C493410:FABP4 protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C039671:ciglitazone