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  Foam cell specific LXRalpha ligand

Feldmann, R., Geikowski, A., Weidner, C., Witzke, A., Kodelja, V., Schwarz, T., et al. (2013). Foam cell specific LXRalpha ligand. PLoS One, 8(2), e57311-e57311. doi:10.1371/journal.pone.0057311.

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 Creators:
Feldmann, R.1, Author           
Geikowski, A.1, Author
Weidner, C.1, Author           
Witzke, A.1, Author           
Kodelja, V.2, Author           
Schwarz, T., Author
Gabriel, M., Author
Erker, T., Author
Sauer, S.1, Author           
Affiliations:
1Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479662              
2Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr, 73, 14195 Berlin, Germany, ou_1433554              

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 Abstract: OBJECTIVE: The liver X receptor alpha (LXRalpha) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis. METHODS AND RESULTS: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRalpha reporter-gene assays. STX4 displayed the unique property to activate LXRalpha effectively but not its subtype LXRbeta. The potential of STX4 to increase transcriptional activity as an LXRalpha ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09. CONCLUSIONS: STX4 is a new LXRalpha-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.

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Language(s): eng - English
 Dates: 2013-02-25
 Publication Status: Published online
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1371/journal.pone.0057311
ISSN: 1932-6203 (Electronic)1932-6203 (Linking)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23451202
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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 8 (2) Sequence Number: - Start / End Page: e57311 - e57311 Identifier: ISSN: 1932-6203
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000277850