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J. Biol. Chem., Vol. 282, Issue 27, 19556-19564, July 6, 2007

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A Dominant Negative Form of the Transcription Factor c-Jun Affects Genes That Have Opposing Effects on Lipid Homeostasis in Mice^*

Konstantinos Drosatos^¶1, Despina Sanoudou^||, Kyriakos E. Kypreos^¶, Dimitris Kardassis^**, and Vassilis I. Zannis^¶2

From the Department of Basic Sciences, University of Crete Medical School, Heraklion GR-71110, Greece, the ^**Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion GR-71110, Greece, ^||Molecular Biology Division, Center for Basic Research, Foundation for Biomedical Research of the Academy of Athens, Athens 11527, Greece, and ^¶Molecular Genetics, Departments of Medicine and Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118

c-Jun is a transcription factor activated by phosphorylation by the stress-activated protein kinase/c-Jun N-terminal kinase pathway in response to extracellular signals and cytokines. We show that adenovirus-mediated gene transfer of the dominant negative form of c-Jun (dn-c-Jun) in C57BL/6 mice increased greatly apoE hepatic mRNA and plasma levels, increased plasma cholesterol, triglyceride, and very low density lipoprotein levels, and resulted in the accumulation of discoidal high density lipoprotein particles. A similar but more severe phenotype was generated by overexpression of the mouse apoE in C57BL/6 mice, suggesting that dyslipidemia induced by dn-c-Jun was the result of apoE overexpression. Unexpectedly, infection of apoE^-/- mice with adenovirus expressing dn-c-Jun reduced plasma cholesterol by 70%, suggesting that dn-c-Jun affected other genes that control plasma cholesterol levels. To identify these genes, we performed whole genome expression analysis (34,000 genes) of isolated livers from two groups of five apoE^-/- mice, infected with adenoviruses expressing either the dn-c-Jun or the green fluorescence protein. Bioinformatic analysis and Northern blotting validation revealed that dn-c-Jun increased 40-fold the apoE mRNA and reduced by 70% the Scd-1 (stearoyl-CoA-desaturase 1) mRNA. The involvement of Scd-1 in lowering plasma cholesterol was confirmed by restoration of high cholesterol levels of apoE^-/- mice following coinfection with adenoviruses expressing dn-c-Jun and Scd-1. In conclusion, dn-c-Jun appears to trigger two opposing events in mice that affect plasma cholesterol and triglyceride levels as follows: one results in apoE overexpression and triggers dyslipidemia and the other results in inhibition of Scd-1 and offsets dyslipidemia.

Received for publication, February 1, 2007 , and in revised form, April 2, 2007.

^* This work was supported by National Institutes of Health Grants HL48739 and HL33952 and the 6th Framework Programme of the European Union LSHM-CT-2006-037631, American Heart Association Grant SDG05354437 (to K. K.), and a grant from the Ministry of Education and the Ministry of Development of Greece (PENED-2001). 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 Figs. 1–8 and Table 1.

¹ Graduate student of the Joint Graduate Program in Molecular Biology and Biomedicine of the Department of Biology and the Basic Science Department of the University of Crete Medical School.

² To whom correspondence should be addressed: 700 Albany St., W509, Boston, MA 02118-2934. Tel.: 617-638-5085; Fax: 617-638-5141; E-mail: vzannis{at}bu.edu.

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