Promoter-Specific Roles for Liver X Receptor/Corepressor Complexes in the Regulation of ABCA1 and SREBP1 Gene Expression

Abstract

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.

ACKNOWLEDGMENTS

We thank A. Zulueta for assistance with preparation of the manuscript and C. Bayne for the production of T1317. We also thank Joyce Repa and David Mangelsdorf for making LXR^−/− mice available for these studies and for critical reading of the manuscript.

These studies were supported by a Biostar grant from the University of California, an NIH grant to the La Jolla Specialized Center of Research on Atherosclerosis (grant HL56989), and a grant from the Stanford Reynolds Center. A.F.V. was supported in part by a grant from the Ministry of Spain (Programa Formación de Personal Investigador en el Extranjero).

B. L. Wagner and A. F. Valledor contributed equally to the preparation of the manuscript and should be considered joint first authors.