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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

jun Genes
Apolipoproteins E
Homeostasis
Transcription Factors
Stearoyl-CoA Desaturase
Lipids
Cholesterol
Plasmas
Adenoviridae
Dyslipidemias
Genes
Inbred C57BL Mouse
Messenger RNA
Gene transfer
Dominant Genes
VLDL Cholesterol
Phosphorylation
JNK Mitogen-Activated Protein Kinases
Liver
HDL Lipoproteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. / Drosatos, Konstantinos; Sanoudou, Despina; Kypreos, Kyriakos E.; Kardassis, Dimitris; Zannis, Vassilis I.

In: Journal of Biological Chemistry, Vol. 282, No. 27, 06.07.2007, p. 19556-19564.

Research output: Contribution to journalArticle

Drosatos, Konstantinos ; Sanoudou, Despina ; Kypreos, Kyriakos E. ; Kardassis, Dimitris ; Zannis, Vassilis I. / A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 27. pp. 19556-19564.
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AB - 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.

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