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Liver X Receptors Interact with Corepressors to Regulate Gene Expression

Department of Biotechnology, Pharmacia Corp., St. Louis, Missouri 63017

Address all correspondence and requests for reprints to: Deepak S. Lala, Ph.D., or Xiao Hu, Ph.D., Mail Zone AA3G, 700 Chesterfield Parkway North, Chesterfield, Missouri 63017. E-mail: Deepak.S.Lala{at}pharmacia.com or Xiao.Hu{at}pharmacia.com.

Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate gene expression in response to oxysterols and play a critical role in cholesterol homeostasis by regulating genes that are involved in cholesterol transport, catabolism, and triglyceride synthesis. Oxysterols and synthetic agonists bind LXRs and activate transcription by recruiting coactivator proteins. The role of LXRs in regulating target gene expression in the absence of ligand is unknown. Here we show that LXRs interact with corepressors, N-CoR (nuclear receptor corepressor) and SMRT (silent mediator of retinoic acid receptor and thyroid receptor), which are released upon binding agonists. The LXR-corepressor interaction is isoform selective, wherein LXR has a very strong interaction with corepressors and LXRß only shows weak interaction. LXRs also exhibit a preference for interacting with N-CoR vs. SMRT. Similar to other nuclear receptors, mutations in the LXR helix 3 and 4 region abolish corepressor interaction. Using a transient transfection assay, we demonstrate that LXR represses transcription that can be further increased by cotransfecting N-CoR into cells. Chromatin immunoprecipitation experiments further indicated that N-CoR is recruited onto endogenous LXR target genes, and addition of LXR agonists releases N-CoR from their promoters. Collectively, these results suggest that corepressors play an important role in regulating LXR target gene expression.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα

Coregulators:   NCOR  |  SMRT

Ligands:   T0901317

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