title: Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo.
abstract: OBJECTIVE
  We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-cholesterol transport (mRCT) in vivo. Because LXR are expressed in multiple tissues involved in RCT (macrophages, liver, intestine), we analyzed the effect of tissue-specific LXR agonism on mRCT.
  
  
  RESULTS
  In initial studies, the systemic LXR agonist GW3965 failed to promote mRCT in a setting in which LXR was expressed in macrophages but not in liver or intestine. To evaluate the effect of LXR activation specifically in small intestine on mRCT, wild-type mice were treated with either intestinal-specific LXR agonist (GW6340) or systemic LXR agonist (GW3965). Both GW3965 and GW6340 significantly promoted excretion of [(3)H]-sterol in feces by 162% and 52%, respectively. To evaluate the requirement for macrophage LXR activation, we assessed the ability of GW3965 to promote mRCT in wild-type mice using primary macrophages deficient in LXR alpha/beta vs wild-type macrophages. Whereas GW3965 treatment promoted fecal excretion compared with vehicle, its overall ability to promote mRCT was significantly attenuated using LXR alpha/beta knockout macrophages.
  
  
  CONCLUSIONS
  We demonstrate that intestinal-specific LXR agonism promotes macrophage RCT in vivo and that macrophage LXR itself plays an important, but not predominant, role in promoting RCT in response to an LXR agonist.
authors.affiliation: Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yasuda
authors.forename: Didier
authors.initials: D
authors.lastname: Grillot
authors.forename: Jeffery T
authors.initials: JT
authors.lastname: Billheimer
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.forename: Philippe
authors.initials: P
authors.lastname: Delerive
authors.forename: Stephane
authors.initials: S
authors.lastname: Huet
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D002784:Cholesterol