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

André R. Miserez*, Patrick Y. Muller, Luca Barella, Sandra Barella, Hannes B. Staehelin, Eran Leitersdorf, Jeremy D. Kark, Yechiel Friedlander

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH2-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.

Original languageEnglish
Pages (from-to)15-26
Number of pages12
JournalAtherosclerosis
Volume164
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Cholesterol homeostasis
  • Cleavage
  • Gene-dose effect
  • Gene-gene interactions
  • Genetics
  • Single-nucleotide polymorphism (SNP)
  • Transcription

Fingerprint

Dive into the research topics of 'Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia'. Together they form a unique fingerprint.

Cite this