title: Macrophage-independent regulation of reverse cholesterol transport by liver X receptors.
abstract: OBJECTIVE
  The ability of high-density lipoprotein (HDL) particles to accept cholesterol from peripheral cells, such as lipid-laden macrophages, and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is thought to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRs; LXRα and LXRβ) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism, and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT, and their tissue-specific contributions to RCT are still not well defined.
  
  
  RESULTS
  Using tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion, we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist-stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function seems to underlie the ability of LXR agonists to stimulate RCT in vivo.
  
  
  CONCLUSIONS
  We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist-stimulated RCT. Unexpectedly, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.
authors.affiliation: From the Department of Pharmacology, University of Virginia, Charlottesville.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Breevoort
authors.affiliation: From the Department of Pharmacology, University of Virginia, Charlottesville.
authors.forename: Jerry
authors.initials: J
authors.lastname: Angdisen
authors.affiliation: From the Department of Pharmacology, University of Virginia, Charlottesville. igs4c@virginia.edu.
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002784:Cholesterol; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C506642:CETP protein, human; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: atherosclerosis; lipoproteins, HDL; macrophages