Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.

Authors:
Prof. Andre R Miserez, MD
Prof. Andre R Miserez, MD
diagene Research Institute
Professor of Internal Medicine, University of Basel
Internal Medicine, Genetics, Metabolomics
Reinach, BL | Switzerland
Patrick Y Muller
Patrick Y Muller
University of Basel
Switzerland
Luca Barella
Luca Barella
Institute of Human Nutrition and Food Science
Germany
Sandra Barella
Sandra Barella
University of California
United States
Hannes B Staehelin
Hannes B Staehelin
University of Basel
Switzerland
Eran Leitersdorf
Eran Leitersdorf
Center for Research
Jeremy D Kark
Jeremy D Kark
Hebrew University-Hadassah School of Public Health and Community Medicine
Jerusalem | Netherlands
Yechiel Friedlander
Yechiel Friedlander
Braun School of Public Health
Australia

Atherosclerosis 2002 Sep;164(1):15-26

Cardiovascular Genetics, Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, University of Basel, Vesalgasse 1, Ch-4051, Basel, Switzerland.

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 (DeltaTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (DeltaTC=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.

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September 2002
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