title: Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading.
abstract: The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-α (NR1H3) and LXRβ (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXRα subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene-selective response to cholesterol loading occurs, even in the presence of LXRα binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXRα to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective.
authors.affiliation: Department of Pharmacology, University of Virginia, 1300 Jefferson Park Avenue, PO Box 800735, Charlottesville, Virginia 22908, USA. igs4c@virginia.edu
authors.forename: Irena D
authors.initials: ID
authors.lastname: Ignatova
authors.forename: Jerry
authors.initials: J
authors.lastname: Angdisen
authors.forename: Erin
authors.initials: E
authors.lastname: Moran
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D008024:Ligands; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol