A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice

Konstantinos Drosatos, Despina Sanoudou, Kyriakos E. Kypreos, Dimitris Kardassis, Vassilis I. Zannis

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    20 Citations (Scopus)

    Abstract

    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, dnc-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.

    Original languageEnglish
    Pages (from-to)19556-19564
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume282
    Issue number27
    DOIs
    Publication statusPublished - 6 Jul 2007

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    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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