Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression.
Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.
Wagner
Brandee L
BL
X-Ceptor Therapeutics, San Diego, California 92121, USA.
Valledor
Annabel F
AF
Shao
Gang
G
Daige
Chris L
CL
Bischoff
Eric D
ED
Petrowski
Mary
M
Jepsen
Kristen
K
Baek
Sung Hee
SH
Heyman
Richard A
RA
Rosenfeld
Michael G
MG
Schulman
Ira G
IG
Glass
Christopher K
CK
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005838:Genotype; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D057093:Orphan Nuclear Receptors; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D013963:Thyroid Hormones / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D022762:CCAAT-Enhancer-Binding Proteins; D008076:Cholesterol, HDL; D002843:Chromatin; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C539128:Ncor1 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013963:Thyroid Hormones; D014157:Transcription Factors; D012313:RNA; D002784:Cholesterol