title: A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice.
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, 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.
authors: Department of Basic Sciences, University of Crete Medical School, Heraklion GR-71110, Greece.
authors: Konstantinos
authors: K
authors: Drosatos
authors: Despina
authors: D
authors: Sanoudou
authors: Kyriakos E
authors: KE
authors: Kypreos
authors: Dimitris
authors: D
authors: Kardassis
authors: Vassilis I
authors: VI
authors: Zannis
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000172:deficiency; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D005799:Genes, Dominant; D016678:Genome; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D048031:JNK Mitogen-Activated Protein Kinases