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Papers In Press, published online ahead of print February 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800376-JLR200

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Journal of Lipid Research, Vol. 50, 312-326, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia^*,

Adelheid Kratzer^*,, Marlene Buchebner^*, Thomas Pfeifer^*, Tatjana M. Becker^*, Georg Uray, Makoto Miyazaki, Shinobu Miyazaki-Anzai, Birgit Ebner^*,**, Prakash G. Chandak^*, Rajendra S. Kadam, Emine Calayir^*, Nora Rathke^*, Helmut Ahammer, Branislav Radovic^*, Michael Trauner^***, Gerald Hoefler, Uday B. Kompella^,, Guenter Fauler^****, Moshe Levi, Sanja Levak-Frank^*, Gerhard M. Kostner^* and Dagmar Kratky^1,*

^* Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21/3, 8010 Graz, Austria
Division of Renal Diseases and Hypertension, University of Colorado at Denver Health Science Center, 4200 East 9th Avenue, Denver, CO 80262
Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
^** Center for Medical Research, Medical University of Graz, Stiftingtalstrasse 24, 8010 Graz, Austria
Department of Pharmaceutical Sciences, University of Colorado at Denver Health Science Center, 4200 East 9th Avenue, Denver, CO 80262
Institute of Biophysics, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria
^*** Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
Department of Ophthalmology, University of Colorado at Denver Health Science Center, 4200 East 9th Avenue, Denver, CO 80262
^**** Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria

^* This work was supported by the Austrian Federal Ministry of Science and Research (Genomforschung Austria Project G.O.L.D.II, Genomics of Lipid-associated Disorders II), the Austrian Science Fund FWF (P19186, SFB-LIPOTOX F3004 and F3001 and SFB F3210-HEART), and the Austrian Nationalbank (10797).

The online version of this article (available at http://www.jlr.org) contains supplementary information and two supplementary figures.

Published, JLR Papers in Press, September 23, 2008.

¹ To whom correspondence should be addressed. e-mail: dagmar.kratky{at}meduni-graz.at

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists.

Supplementary key words atherogenesis • liver X receptor • cholesterol catabolism • ABC transporter • gene expression

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