Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia
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-dens...
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| creator | Miserez, André R. Muller, Patrick Y. Barella, Luca Barella, Sandra Staehelin, Hannes B. Leitersdorf, Eran Kark, Jeremy D. Friedlander, Yechiel |
| description | 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. |
| doi_str_mv | 10.1016/S0021-9150(01)00762-6 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9150</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/S0021-9150(01)00762-6</identifier><identifier>PMID: 12119189</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ireland Ltd</publisher><subject>Adolescent ; Adult ; Biological and medical sciences ; Blotting, Western ; Cholesterol homeostasis ; Cleavage ; Disorders of blood lipids. Hyperlipoproteinemia ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Female ; Gene Expression Regulation ; Genetics ; Gene–dose effect ; Gene–gene interactions ; Genotype ; Humans ; Hypercholesterolemia - genetics ; Hypercholesterolemia - metabolism ; Male ; Medical sciences ; Metabolic diseases ; Polymorphism, Single Nucleotide ; Prevalence ; Protein Isoforms ; Protein Structure, Secondary ; Single-nucleotide polymorphism (SNP) ; Sterol Regulatory Element Binding Protein 2 ; Transcription ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcriptional Activation</subject><ispartof>Atherosclerosis, 2002-09, Vol.164 (1), p.15-26</ispartof><rights>2002 Elsevier Science Ltd</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-ce65be88a8f0b1ff26b94c50e8f94d451366595e94a33f20655a1a15ebdcc95c3</citedby><cites>FETCH-LOGICAL-c443t-ce65be88a8f0b1ff26b94c50e8f94d451366595e94a33f20655a1a15ebdcc95c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0021-9150(01)00762-6$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13807371$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12119189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miserez, André R.</creatorcontrib><creatorcontrib>Muller, Patrick Y.</creatorcontrib><creatorcontrib>Barella, Luca</creatorcontrib><creatorcontrib>Barella, Sandra</creatorcontrib><creatorcontrib>Staehelin, Hannes B.</creatorcontrib><creatorcontrib>Leitersdorf, Eran</creatorcontrib><creatorcontrib>Kark, Jeremy D.</creatorcontrib><creatorcontrib>Friedlander, Yechiel</creatorcontrib><title>Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description>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.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cholesterol homeostasis</subject><subject>Cleavage</subject><subject>Disorders of blood lipids. Hyperlipoproteinemia</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Genetics</subject><subject>Gene–dose effect</subject><subject>Gene–gene interactions</subject><subject>Genotype</subject><subject>Humans</subject><subject>Hypercholesterolemia - genetics</subject><subject>Hypercholesterolemia - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Prevalence</subject><subject>Protein Isoforms</subject><subject>Protein Structure, Secondary</subject><subject>Single-nucleotide polymorphism (SNP)</subject><subject>Sterol Regulatory Element Binding Protein 2</subject><subject>Transcription</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional Activation</subject><issn>0021-9150</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMFu1DAURS1ERYfCJ4CyAbULF7_ETuwVgqrQSpVADKwtx3mZGjn21HaQ5u9JZ0Z0yeptzr3v6hDyBtglMGg_rBmrgSoQ7JzBBWNdW9P2GVmB7BQFLvlzsvqHnJKXOf9mjPEO5AtyCjWAAqlWpF8XTNHThJvZmxLTrkKPE4ZCexcGFzbVNsWCLlTn6x_Xn79f0LqyMZTk-rlgrkqsttHvNhicre53W0z2PnrM-1qDkzOvyMlofMbXx3tGfn25_nl1Q---fb29-nRHLedNoRZb0aOURo6sh3Gs215xKxjKUfGBC2jaViiBipumGWvWCmHAgMB-sFYJ25yR94feZfDDvCzQk8sWvTcB45x1B4pJxbsFFAfQpphzwlFvk5tM2mlg-lGu3svVj-Y0A72Xq9sl9_b4YO4nHJ5SR5sL8O4ImGyNH5MJ1uUnrpGsazpYuI8HDhcdfxwmna3DYHFwCW3RQ3T_mfIXToCXUw</recordid><startdate>20020901</startdate><enddate>20020901</enddate><creator>Miserez, André R.</creator><creator>Muller, Patrick Y.</creator><creator>Barella, Luca</creator><creator>Barella, Sandra</creator><creator>Staehelin, Hannes B.</creator><creator>Leitersdorf, Eran</creator><creator>Kark, Jeremy D.</creator><creator>Friedlander, Yechiel</creator><general>Elsevier Ireland Ltd</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020901</creationdate><title>Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia</title><author>Miserez, André R. ; Muller, Patrick Y. ; Barella, Luca ; Barella, Sandra ; Staehelin, Hannes B. ; Leitersdorf, Eran ; Kark, Jeremy D. ; Friedlander, Yechiel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-ce65be88a8f0b1ff26b94c50e8f94d451366595e94a33f20655a1a15ebdcc95c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cholesterol homeostasis</topic><topic>Cleavage</topic><topic>Disorders of blood lipids. Hyperlipoproteinemia</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Genetics</topic><topic>Gene–dose effect</topic><topic>Gene–gene interactions</topic><topic>Genotype</topic><topic>Humans</topic><topic>Hypercholesterolemia - genetics</topic><topic>Hypercholesterolemia - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Prevalence</topic><topic>Protein Isoforms</topic><topic>Protein Structure, Secondary</topic><topic>Single-nucleotide polymorphism (SNP)</topic><topic>Sterol Regulatory Element Binding Protein 2</topic><topic>Transcription</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional Activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miserez, André R.</creatorcontrib><creatorcontrib>Muller, Patrick Y.</creatorcontrib><creatorcontrib>Barella, Luca</creatorcontrib><creatorcontrib>Barella, Sandra</creatorcontrib><creatorcontrib>Staehelin, Hannes B.</creatorcontrib><creatorcontrib>Leitersdorf, Eran</creatorcontrib><creatorcontrib>Kark, Jeremy D.</creatorcontrib><creatorcontrib>Friedlander, Yechiel</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miserez, André R.</au><au>Muller, Patrick Y.</au><au>Barella, Luca</au><au>Barella, Sandra</au><au>Staehelin, Hannes B.</au><au>Leitersdorf, Eran</au><au>Kark, Jeremy D.</au><au>Friedlander, Yechiel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2002-09-01</date><risdate>2002</risdate><volume>164</volume><issue>1</issue><spage>15</spage><epage>26</epage><pages>15-26</pages><issn>0021-9150</issn><eissn>1879-1484</eissn><abstract>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.</abstract><cop>Amsterdam</cop><pub>Elsevier Ireland Ltd</pub><pmid>12119189</pmid><doi>10.1016/S0021-9150(01)00762-6</doi><tpages>12</tpages></addata></record> |
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| subjects | Adolescent Adult Biological and medical sciences Blotting, Western Cholesterol homeostasis Cleavage Disorders of blood lipids. Hyperlipoproteinemia DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Female Gene Expression Regulation Genetics Gene–dose effect Gene–gene interactions Genotype Humans Hypercholesterolemia - genetics Hypercholesterolemia - metabolism Male Medical sciences Metabolic diseases Polymorphism, Single Nucleotide Prevalence Protein Isoforms Protein Structure, Secondary Single-nucleotide polymorphism (SNP) Sterol Regulatory Element Binding Protein 2 Transcription Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Activation |
| title | Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia |
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