© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements
From the Department of Clinical Chemistry (H.G., M.N., R.S., C.S., H.S., H.W., W.M.), University Hospital Freiburg, Freiburg, Germany; the Department of Research (M.R.), University Hospital Basel, Basel, Switzerland; and the Faculty of Biology (H.G., G.N.), Institute for Biology II/Cell Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
Correspondence to Dr Markus Nauck, University Hospital Freiburg, Department of Clinical Chemistry, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail msnauck{at}med1.ukl.uni-freiburg.de
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 125I-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.
Key Words: transcription factors • cholesterol • lipoproteins • receptors • hypocholesterolemia
This article has been cited by other articles:
 |
|
 |
|
  B. Morin, L. A. Nichols, K. M. Zalasky, J. W. Davis, J. A. Manthey, and L. J. Holland The Citrus Flavonoids Hesperetin and Nobiletin Differentially Regulate Low Density Lipoprotein Receptor Gene Transcription in HepG2 Liver Cells J. Nutr., July 1, 2008; 138(7): 1274 - 1281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Mahoney, A. Safdar, G. Parise, S. Melov, M. Fu, L. MacNeil, J. Kaczor, E. T. Payne, and M. A. Tarnopolsky Gene expression profiling in human skeletal muscle during recovery from eccentric exercise Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1901 - R1910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Poree, M. Kypriotou, C. Chadjichristos, G. Beauchef, E. Renard, F. Legendre, M. Melin, S. Gueret, D.-J. Hartmann, F. Mallein-Gerin, et al. Interleukin-6 (IL-6) and/or Soluble IL-6 Receptor Down-regulation of Human Type II Collagen Gene Expression in Articular Chondrocytes Requires a Decrease of Sp1{middle dot}Sp3 Ratio and of the Binding Activity of Both Factors to the COL2A1 Promoter J. Biol. Chem., February 22, 2008; 283(8): 4850 - 4865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E Kasim-Karakas, A. Tsodikov, U. Singh, and I. Jialal Responses of inflammatory markers to a low-fat, high-carbohydrate diet: effects of energy intake. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 774 - 779. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cai, T. S. Hatsukami, M. S. Ferguson, W. S. Kerwin, T. Saam, B. Chu, N. Takaya, N. L. Polissar, and C. Yuan In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque: Comparison of High-Resolution, Contrast-Enhanced Magnetic Resonance Imaging and Histology Circulation, November 29, 2005; 112(22): 3437 - 3444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Liberopoulos, F. Apostolou, and M. Elisaf Serum lipid profile in patients with severe leptospirosis Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1328 - 1329. [Full Text] [PDF]
|
|
|
|
|
|
C. Manzoni, M. Duranti, I. Eberini, H. Scharnag, W. Marz, S. Castiglioni, and M. R. Lovati Subcellular Localization of Soybean 7S Globulin in HepG2 Cells and LDL Receptor Up-Regulation by Its {alpha}' Constituent Subunit J. Nutr., July 1, 2003; 133(7): 2149 - 2155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Lin, L. Zeng, Y. Liu, K. DeFea, M. A. Schwartz, S. Chien, and J. Y.-J. Shyy Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins Circ. Res., June 27, 2003; 92(12): 1296 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, F. Zhang, C. Li, M. Lin, and M. R. Briggs Synergistic Activation of Human LDL Receptor Expression by SCAP Ligand and Cytokine Oncostatin M Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 90 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Cai, T. S. Hatsukami, M. S. Ferguson, R. Small, N. L. Polissar, and C. Yuan Classification of Human Carotid Atherosclerotic Lesions With In Vivo Multicontrast Magnetic Resonance Imaging Circulation, September 10, 2002; 106(11): 1368 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhang, T. E. Ahlborn, C. Li, F. B. Kraemer, and J. Liu Identification of Egr1 as the oncostatin M-induced transcription activator that binds to sterol-independent regulatory element of human LDL receptor promoter J. Lipid Res., September 1, 2002; 43(9): 1477 - 1485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Feister, B. J. Auerbach, L. A. Cole, B. R. Krause, and S. K. Karathanasis Identification of an IL-6 response element in the human LCAT promoter J. Lipid Res., June 1, 2002; 43(6): 960 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
|
|