Mutation in the Gene Encoding Sterol Regulatory Element Binding Protein (SREBP-2) in Hyper-Cholesterolaemic Subjects (original) (raw)
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Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia
Atherosclerosis, 2002
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 receptormediated 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 0/1334) and Israel (N 0/923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC (P0/0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (DTC 0/1.05 mmol/l, 14.4%; P 0/0.002; N 0/477), but absent in normocholesterolaemic subjects (DTC 0/0.06 mmol/l, 1.4%; P0/0.334; N 0/1780). 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. #
Biomedicines
Patients with high cholesterol and glucose levels are at high risk for cardiovascular disease. The Sterol Regulatory Element Binding Protein (SREBP) system regulates genes involved in lipid, cholesterol and glucose pathways. Autosomal Dominant Hypercholesterolemias (ADHs) are a group of diseases with increased cholesterol levels. They affect 1 out of every 500 individuals. About 20–30% of patients do not present any mutation in the known genes (LDLR, APOB and PCSK9). ADHs constitute a good model to identify the genes involved in the alteration of lipid levels or possible therapeutic targets. In this paper, we studied whether a mutation in the SREBP system could be responsible for ADH and other metabolic alterations present in these patients. Forty-one ADH patients without mutations in the main responsible genes were screened by direct sequencing of SREBP system genes. A luciferase reporter assay of the found mutation and an oral glucose tolerance test in carriers and non-carriers we...
Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man
2006
Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C-G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia. Thus, our aim was to study effect of the SREBF-1 gene polymorphism (G952G) on sterol metabolism in man.
Gene, 2012
Familial hypercholesterolemia (FH), Niemann-Pick disease type C (NPC) and Tangier disease (TD) are genetic inherited disorders with impaired processing of cholesterol, caused by mutations in genes that regulate cellular uptake, intracellular movement and transport of cholesterol. Various studies have shown a crucial regulatory role of the SREBP-pathway for cellular cholesterol homeostasis in these diseases. Since cholesterol is an essential structural component of cells, we assessed the impact of a severe FH causing LDLR mutation (FH p.W556R) on the SREBP pathway in primary FH fibroblasts. Primary FH fibroblasts derived from patients with the LDL receptor mutation p.W556R were used for gene expression experiments. Gene expression studies revealed increased expressions of SREBP regulated genes HMGCR, LDLR, SREBP-2, SREBP-1, SR-BI, INSIG-1, but interestingly not SCAP. In contrast expression of ABCA1, was strongly decreased in homozygous, but not in heterozygous p.W556R fibroblasts. Gene expression experiments with LDL receptor lacking primary FH fibroblasts, revealed that SR-BI and ABCA1 are important regulators for cholesterol acquisition in FH cells, consistent with findings in cells from NPC and TD patients.
Atherosclerosis, 2011
Objective: Alterations of lipid metabolism play a pivotal role in the development of atherosclerosis and its complications, today's major mortality risks. The predominant regulators controlling cholesterol-and fatty acids synthesis in liver are the sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that were formerly identified as cholesterol sensor for LDLR gene expression. Variation of gene structure in these genes might therefore indicate a predisposition to develop complications like myocardial infarction and stroke. Methods: We investigated 190 unrelated German subjects, including 69 subjects with LDL-cholesterol <55 mg/dl, for mutations in SREBP genes SREBF-1 and SREBF-2 by direct sequencing. The impact on SREBP functionality was analyzed by protein biochemical analyses, promoter reporter gene assays and gene expression studies. Results: A missense mutation in SREBF-1 (c.332 C>T; P111L) was identified in a subject with LDLcholesterol <5 mg/dl. Examination of the subject's family confirmed the mutation in two of three siblings. Detailed clinical evaluation of these subjects disclose a novel form of primary combined hypolipidemia only in SREBP-1a P111L carriers, characterized by low levels of apoB and apoA1, low triglyceride, LDL-cholesterol and HDL-cholesterol levels. Functional analyses indicated that the mutation abolishes phosphorylation of SREBP-1. As a consequence transcriptional activation of classical target genes, i.e. LDLR, HMG-CoAR, FAS, ABCA1, but also MTTP, was dramatically reduced. Conclusions: Phosphorylation of SREBP-1, the master regulator of genes for central rate limiting enzymes of cholesterol and lipid metabolism, appears to be a biological principle with clinical implications.
Endocrinology, 1999
The high density lipoprotein (HDL) receptor, or scavenger receptor class B type I (SR-BI), is critical for cholesterol transport and a potential target for hypercholesterolemic drugs. Thus, elucidation of the mechanism underlying regulation of the HDL receptor SR-BI gene is essential. It has been previously shown that there is a correlation between depletion in ovarian cholesteryl ester content and increased HDL receptor SR-BI expression in response to hormonal stimulation. We wanted to determine whether the levels of mature sterol response element-binding protein-1a (SREBP-1a), a key protein in the transcriptional regulation of several genes by sterols, are affected under these conditions. Thus, Western blot analysis was carried out. Consistent with the possibility that SREBP-1a may be involved in the regulation of the HDL receptor SR-BI gene, we found that mature SREBP-1a levels increased up to 11-fold in the ovary after treatment with 50 U hCG. This increase in mature SREBP-1a protein levels correlated with a 30% decrease in ovarian cholesterol levels. These changes in both SREBP-1a and cholesterol levels preceded a 2-fold induction of HDL receptor SR-BI protein levels. To determine whether SREBP-1a could directly regulate the expression of the rat
Human …, 2006
Sterol regulatory element binding protein 1 (SREBP-1) transcription factors play a key role in energy homeostasis by regulating genes involved in both carbohydrate and lipid metabolism, and in adipocyte differentiation. The 5' end of the mRNA-encoding SREBP-1 exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5' exons, each of which is spliced to a common exon 2. Mutations in the sterol regulatory element binding protein gene (SREBF)-1 may contribute to insulin resistance states. However, the variants described to date do not affect the SREBP function. In this study, we investigated the functional consequences of a novel missense mutation common to both SREBP-1 isoforms identified in a Spanish Type 2 diabetic patient (c.677C>T, SREBP-1a p.T226M; c.605C>T, SREBP-1c p.T202M). Using reporter gene analysis and electrophoretic mobility shift assays, we found that this variant impaires the transcriptional activity and reduces DNA binding ability despite its comparable protein stability to the wild-type SREBP-1. This decreased activity impaires the expression of known downstream targets, such as the LDL receptor and fatty acid synthase genes. Our findings suggest that the threonine residue and/or surrounding region play an important role in the SREBP-1 function.".
Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein
Cell, 1996
a transcription factor of the basic-helix-loop-helixleucine zipper family, a middle segment of approxi-Joseph L. Goldstein, and Michael S. Brown mately 75 amino acids composed of two membrane-Department of Molecular Genetics spanning regions separated by a short hydrophilic loop University of Texas Southwestern Medical Center of 31 amino acids, and a carboxy-terminal segment of Dallas, Texas 75235 approximately 500 amino acids that plays a regulatory role . The SREBPs are oriented in the membranes of the endoplas-Summary mic reticulum (ER) and nuclear envelope in a hairpin fashion, so that the NH 2 -terminal and carboxy-terminal Through expression cloning we have isolated a cDNAsegments project into the cytosol and the 31 amino acid encoding SREBP cleavage-activating protein (SCAP), loop projects into the lumen (Hua et al., 1995). In cultured which regulates cholesterol metabolism by stimulatcells the two SREBPs act independently, and they are ing cleavage of transcription factors SREBP-1 and -2, apparently redundant. thereby releasing them from membranes. The cDNA