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J. Biol. Chem., Vol. 283, Issue 33, 22723-22736, August 15, 2008

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Activation of Liver X Receptors Prevents Statin-induced Death of 3T3-L1 Preadipocytes^*

Lise Madsen¹², Rasmus K. Petersen^¶1, Knut R. Steffensen^||, Lone M. Pedersen, Philip Hallenborg, Tao Ma, Livar Frøyland, Stein Ove Døskeland^**, Jan-Åke Gustafsson^||, and Karsten Kristiansen³

From the Department of Biochemistry and Molecular Biology, Campusvej55, University of Southern Denmark, 5230O denseM, Denmark, the National Institute of Nutrition and Seafood Research, Postboks 2029, 5817 Bergen, Norway, ^¶BioLigands, International Science Park, 5230 Odense, Denmark, the ^||Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, 14157 Huddinge, Sweden, and the ^**Department of Biomedicine, Medical Faculty, University of Bergen, 5097 Bergen, Norway

The biological functions of liver X receptors (LXRs) and β have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXR^+/+/LXRβ^+/+), LXR knock-out mice (LXR^-/-/LXRβ^+/+), LXRβ knock-out mice (LXR^+/-/LXRβ^-/-), and LXR double knock-out mice (LXR^-/-/LXRβ^-/-) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXR or a dominant negative version of LXR, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-B activity, since expression of a dominant negative version of IB prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.

Received for publication, January 28, 2008 , and in revised form, May 16, 2008.

^* This work was supported by the Danish Natural Science Research Council, the Norwegian Research Council, and the NOVO Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Fax: 47-55-90-52-99; E-mail: lise.madsen{at}bmb.sdu.dk.

³ To whom correspondence may be addressed. Fax: 45-6550-2467; E-mail: kak{at}bmb.sdu.dk.

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