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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2009.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Effect of Macrophage Overexpression of Murine Liver X Receptor- (LXR-) on Atherosclerosis in LDL-Receptor Deficient Mice

Daniel Teupser; Daniel Kretzschmar; Carsten Tennert; Ralph Burkhardt; Wolfgang Wilfert; Dörte Fengler; Ronald Naumann; Albrecht E. Sippel; Joachim Thiery

From the Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (D.T., D.K., C.T., R.B., W.W., D.F., J.T.) University Leipzig, Germany; Institut für Biologie III (A.E.S.), Albrecht-Ludwigs-Universität Freiburg, Germany; and the Max Planck Institute of Molecular Cell Biology and Genetics (R.N.), Dresden, Germany.

Correspondence to Dr Daniel Teupser, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics; University Leipzig; Liebigstr. 27, 04103 Leipzig, Germany. E-mail teupser{at}medizin.uni-leipzig.de

Background— The nuclear liver X receptor- (LXR-) 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- might affect these mechanisms and result in a reduction of atherosclerosis.

Methods and Results— We generated mice with macrophage overexpression of mouse LXR-, 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- 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.

Conclusion— Our data show for the first time that transgenic overexpression of LXR- in macrophages has significant antiatherogenic properties. We conclude that overexpression of LXR- in macrophages might be useful as a therapeutic principle for the prevention of atherosclerosis.

We demonstrate for the first time that macrophage overexpression of murine LXR- in LDLR^–/– mice reduces the development of peripheral atherosclerosis, modulates inflammatory response, and enhances cholesterol efflux in bone marrow–derived macrophages.

Key Words: macrophages • LXR- • atherosclerosis • transgenic mouse

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