Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia
| Autor: | André R. Miserez, Eran Leitersdorf, Hannes B. Staehelin, Patrick Y. Muller, Sandra Barella, Luca Barella, Jeremy D. Kark, Yechiel Friedlander |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Male Transcriptional Activation endocrine system medicine.medical_specialty Adolescent Genotype Blotting Western Hypercholesterolemia Population Polymorphism Single Nucleotide Protein Structure Secondary chemistry.chemical_compound Internal medicine Prevalence medicine Humans Protein Isoforms education education.field_of_study biology Cholesterol Binding protein HEK 293 cells Sterol Sterol regulatory element-binding protein DNA-Binding Proteins Endocrinology Gene Expression Regulation chemistry HMG-CoA reductase biology.protein Female lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Sterol Regulatory Element Binding Protein 2 Transcription Factors Lipoprotein |
| Zdroj: | Atherosclerosis. 164:15-26 |
| ISSN: | 0021-9150 |
| Popis: | Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH 2 -terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland ( N =1334) and Israel ( N =923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC ( P =0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (ΔTC=1.05 mmol/l, 14.4%; P =0.002; N =477), but absent in normocholesterolaemic subjects (ΔTC=0.06 mmol/l, 1.4%; P =0.334; N =1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia. |
| Databáze: | OpenAIRE |
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