Activation of liver X receptors prevents statin-induced death of 3t3-L1 preadipocytes

Lise Madsen, Rasmus K. Petersen, Knut R. Steffensen, Lone M. Pedersen, Philip Hallenborg, Tao Ma, Livar Frøyland, Stein Ove Døskeland, Jan Åke Gustafsson, Karsten Kristiansen

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The biological functions of liver X receptors (LXRs) α 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 (LXRβ+/+/LXRβ+/+), LXRα knock-out mice (LXŔ-/-/LXRβ+/+), LXRβ knock-out mice (LXRα+/-/LXRβ-/-), and LXR double knock-out mice (LXRβ-/-/LXRβ-/-) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRα or a dominant negative version of LXRα, 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-κB activity, since expression of a dominant negative version of IκBα 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.

Original languageEnglish (US)
Pages (from-to)22723-22736
Number of pages14
JournalJournal of Biological Chemistry
Volume283
Issue number33
DOIs
StatePublished - Aug 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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