Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice.
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.
Teupser
Daniel
D
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Leipzig, Germany. teupser@medizin.uni-leipzig.de
Kretzschmar
Daniel
D
Tennert
Carsten
C
Burkhardt
Ralph
R
Wilfert
Wolfgang
W
Fengler
Dörte
D
Naumann
Ronald
R
Sippel
Albrecht E
AE
Thiery
Joachim
J
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
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