Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gierens, H; Nauck, M; Roth, M; Schinker, R; Schürmann, C; Scharnagl, H; Neuhaus, G; Wieland, H; März, W.
Interleukin-6 stimulates LDL receptor gene expression via activation of sterol-responsive and Sp1 binding elements.
ARTERIOSCLER THROMB VASC BIOL 2000 20: 1777-1783.
Doi: 10.1161/01.ATV.20.7.1777
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- Co-Autor*innen der Med Uni Graz
- März Winfried
- Scharnagl Hubert
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- Abstract:
- Inflammatory or malignant diseases are associated with elevated levels of cytokines and abnormal low density lipoprotein (LDL) cholesterol metabolism. In the acute-phase response to myocardial injury or other trauma or surgery, total and LDL cholesterol levels are markedly decreased. We investigated the effects of the proinflammatory cytokine interleukin (IL)-6 on LDL receptor (LDL-R) function and gene expression in HepG2 cells. IL-6 dose-dependently increased the binding, internalization, and degradation of (125)I-LDL. IL-6-stimulated HepG2 cells revealed increased steady-state levels of LDL-R mRNA. In HepG2 cells transiently transfected with reporter gene constructs harboring the sequence of the LDL-R promoter extending from nucleotide -1563 (or from nucleotide -234) through -58 relative to the translation start site, IL-6 dose-dependently increased promoter activity. In the presence of LDL, a similar relative stimulatory effect of IL-6 was observed. Studies using a reporter plasmid with a functionally disrupted sterol-responsive element (SRE)-1 revealed a reduced stimulatory response to IL-6. In gel-shift assays, nuclear extracts of IL-6-treated HepG2 cells showed an induced binding of SRE binding protein (SREBP)-1a and SRE binding protein(SREBP)-2 to the SRE-1 that was independent of the cellular sterol content and an induced binding of Sp1 and Sp3 to repeat 3 of the LDL-R promoter. Our data indicate that IL-6 induces stimulation of the LDL-R gene, resulting in enhanced gene transcription and LDL-R activity. This effect is sterol independent and involves, on the molecular level, activation of nuclear factors binding to SRE-1 and the Sp1 binding site in repeat 2 and repeat 3 of the LDL-R promoter, respectively.
- Find related publications in this database (using NLM MeSH Indexing)
- Blotting, Northern -
- CCAAT-Enhancer-Binding Proteins -
- Cells, Cultured -
- DNA-Binding Proteins - genetics
- Dose-Response Relationship, Drug - genetics
- Gene Expression Regulation - drug effects
- Humans - drug effects
- Hypercholesterolemia - metabolism
- Interleukin-6 - pharmacology
- Iodine Radioisotopes - diagnostic use
- Liver - cytology
- Nuclear Proteins - genetics
- Phosphorus Radioisotopes - diagnostic use
- Promoter Regions (Genetics) - physiology
- RNA, Messenger - metabolism
- Receptors, LDL - genetics
- Research Support, Non-U.S. Gov't - genetics
- Sp1 Transcription Factor - genetics
- Sp3 Transcription Factor - genetics
- Sterol Regulatory Element Binding Protein 1 - genetics
- Sterol Regulatory Element Binding Protein 2 - genetics
- Transcription Factors - genetics
- Transcription, Genetic - drug effects
- Transfection - drug effects
- Find related publications in this database (Keywords)
- transcription factors
- cholesterol
- lipoproteins
- receptors
- hypocholesterolemia