title: Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists.
abstract: OBJECTIVE
  Complications of atherosclerotic cardiovascular disease due to elevated blood cholesterol levels are the major cause of death in the Western world. The liver X receptors, LXRalpha and LXRbeta (LXRs), are ligand-dependent transcription factors that act as cholesterol sensors and coordinately control transcription of genes involved in cholesterol and lipid homeostasis as well as macrophage inflammatory gene expression. LXRs regulate cholesterol balance through activation of ATP-binding cassette transporters that promote cholesterol transport and excretion from the liver, intestine, and macrophage. Although LXR agonists are known to delay progression of atherosclerosis in mouse models, their ability to abrogate preexisting cardiovascular disease by inducing regression and stabilization of established atherosclerotic lesions has not been addressed.
  
  
  RESULTS
  We demonstrate that LXR agonist treatment increases ATP-binding cassette transporter expression within preexisting atherosclerotic lesions, resulting in regression of these lesions as well as remodeling from vulnerable to stable lesions and a reduction in macrophage content. Further, using macrophage-selective LXR-deficient mice created by bone marrow transplantation, we provide the first evidence that macrophage LXR expression is necessary for the atheroprotective actions of an LXR agonist.
  
  
  CONCLUSIONS
  These data substantiate that drugs targeting macrophage LXR activity may offer therapeutic benefit in the treatment of atherosclerotic cardiovascular disease.
authors.affiliation: X-Ceptor Therapeutics Inc, San Diego, Calif 92121, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Levin
authors.forename: Eric D
authors.initials: ED
authors.lastname: Bischoff
authors.forename: Chris L
authors.initials: CL
authors.lastname: Daige
authors.forename: Diane
authors.initials: D
authors.lastname: Thomas
authors.forename: Calvin T
authors.initials: CT
authors.lastname: Vu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000473:pathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000172:deficiency; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008264:Macrophages / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000172:deficiency; D012074:Remission Induction / Q000379:methods; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides