title: Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice.
abstract: Background- The nuclear liver X receptor-alpha (LXR-alpha) has been implicated in the regulation of intracellular cholesterol homeostasis, inflammatory response, and atherosclerosis susceptibility. The aim of the present study was to test whether transgenic expression of LXR-alpha might affect these mechanisms and result in a reduction of atherosclerosis.
  
  
  RESULTS
  We generated mice with macrophage overexpression of mouse LXR-alpha, evidenced by significantly elevated expression levels of LXR-target genes (ABCA1, ABCG1) in these cells. For atherosclerosis studies, mice were crossed onto the LDL-receptor deficient background. Plasma lipids and lipoproteins as well as liver triglycerides were not significantly different between transgenic animals and nontransgenic controls. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (-83%, P=0.02) in male LXR-alpha transgenic mice. This was associated with a significantly increased cholesterol efflux to acceptor-free media (+24%, P=0.002) and ApoA1 containing media (+20%, P<0.0001) as well as reduced lipopolysaccharide (LPS)-induced NO-release from macrophages of transgenic animals, providing a potential mechanism for the reduction of atherosclerosis.
  
  
  CONCLUSIONS
  Our data show for the first time that transgenic overexpression of LXR-alpha in macrophages has significant antiatherogenic properties. We conclude that overexpression of LXR-alpha in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Leipzig, Germany. teupser@medizin.uni-leipzig.de
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.forename: Daniel
authors.initials: D
authors.lastname: Kretzschmar
authors.forename: Carsten
authors.initials: C
authors.lastname: Tennert
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wilfert
authors.forename: Dörte
authors.initials: D
authors.lastname: Fengler
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Albrecht E
authors.initials: AE
authors.lastname: Sippel
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016122:Brachiocephalic Trunk / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D009569:Nitric Oxide