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Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice.
Arterioscler Thromb Vasc Biol. 2008 Nov; 28(11):2009-15.AT

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.

METHODS AND 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+Show Affiliations

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Leipzig, Leipzig, Germany. teupser@medizin.uni-leipzig.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18787185

Citation

Teupser, Daniel, et al. "Effect of Macrophage Overexpression of Murine Liver X Receptor-alpha (LXR-alpha) On Atherosclerosis in LDL-receptor Deficient Mice." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, 2008, pp. 2009-15.
Teupser D, Kretzschmar D, Tennert C, et al. Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. Arterioscler Thromb Vasc Biol. 2008;28(11):2009-15.
Teupser, D., Kretzschmar, D., Tennert, C., Burkhardt, R., Wilfert, W., Fengler, D., Naumann, R., Sippel, A. E., & Thiery, J. (2008). Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(11), 2009-15. https://doi.org/10.1161/ATVBAHA.108.175257
Teupser D, et al. Effect of Macrophage Overexpression of Murine Liver X Receptor-alpha (LXR-alpha) On Atherosclerosis in LDL-receptor Deficient Mice. Arterioscler Thromb Vasc Biol. 2008;28(11):2009-15. PubMed PMID: 18787185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of macrophage overexpression of murine liver X receptor-alpha (LXR-alpha) on atherosclerosis in LDL-receptor deficient mice. AU - Teupser,Daniel, AU - Kretzschmar,Daniel, AU - Tennert,Carsten, AU - Burkhardt,Ralph, AU - Wilfert,Wolfgang, AU - Fengler,Dörte, AU - Naumann,Ronald, AU - Sippel,Albrecht E, AU - Thiery,Joachim, Y1 - 2008/09/11/ PY - 2008/9/13/pubmed PY - 2008/11/7/medline PY - 2008/9/13/entrez SP - 2009 EP - 15 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 28 IS - 11 N2 - UNLABELLED: 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. METHODS AND 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/18787185/Effect_of_macrophage_overexpression_of_murine_liver_X_receptor_alpha__LXR_alpha__on_atherosclerosis_in_LDL_receptor_deficient_mice_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.108.175257?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -