Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements
- 1 July 2000
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 20 (7), 1777-1783
- https://doi.org/10.1161/01.atv.20.7.1777
Abstract
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.Keywords
This publication has 25 references indexed in Scilit:
- Structural and functional analyses of DNA bending induced by Sp1 family transcription factorsJournal of Molecular Biology, 1997
- Circulating Levels of Cytokines and Their Endogenous Modulators in Patients With Mild to Severe Congestive Heart Failure Due to Coronary Artery Disease or HypertensionJournal of the American College of Cardiology, 1996
- SREBP-1 Mediates Activation of the Low Density Lipoprotein Receptor Promoter by Insulin and Insulin-like Growth Factor-IOnline Journal of Public Health Informatics, 1996
- Hairpin Orientation of Sterol Regulatory Element-binding Protein-2 in Cell Membranes as Determined by Protease ProtectionOnline Journal of Public Health Informatics, 1995
- Effects of endotoxin and cytokines on lipid metabolismCurrent Opinion in Lipidology, 1994
- Elevated plasma interleukin-6 levels in patients with acute myocardial infarctionAmerican Heart Journal, 1993
- Accumulation of "small dense" low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor.JCI Insight, 1993
- Transforming growth factor-β1 and interleukin-1β stimulate LDL receptor activity in Hep G2 cellsAtherosclerosis, 1992
- Regulation of the mevalonate pathwayNature, 1990
- A Receptor-Mediated Pathway for Cholesterol HomeostasisScience, 1986