Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.
Identifieur interne : 000157 ( Ncbi/Curation ); précédent : 000156; suivant : 000158Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.
Auteurs : Kristin L. Bowden [Canada] ; Nicolas J. Bilbey ; Leanne M. Bilawchuk ; Emmanuel Boadu ; Rohini Sidhu ; Daniel S. Ory ; Hong Du ; Teddy Chan ; Gordon A. FrancisSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2011.
Descripteurs français
- KwdFr :
- Chloroquine (métabolisme), Cholestérol (métabolisme), Fibroblastes (métabolisme), Humains, Lipoprotéines (métabolisme), Lipoprotéines HDL (métabolisme), Maladie de Wolman (génétique), Maladie de Wolman (métabolisme), Maladie de stockage des esters de cholestérol (génétique), Maladie de stockage des esters de cholestérol (métabolisme), Milieux de culture conditionnés (pharmacologie), Mutation, Peau (métabolisme), Phospholipides (métabolisme), Protéines recombinantes (métabolisme), Stérols (), Transporteur-1 à cassette liant l'ATP, Transporteurs ABC (métabolisme).
- MESH :
- génétique : Maladie de Wolman, Maladie de stockage des esters de cholestérol.
- métabolisme : Chloroquine, Cholestérol, Fibroblastes, Lipoprotéines, Lipoprotéines HDL, Maladie de Wolman, Maladie de stockage des esters de cholestérol, Peau, Phospholipides, Protéines recombinantes, Transporteurs ABC.
- pharmacologie : Milieux de culture conditionnés.
- Humains, Mutation, Stérols, Transporteur-1 à cassette liant l'ATP.
English descriptors
- KwdEn :
- ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters (metabolism), Chloroquine (metabolism), Cholesterol (metabolism), Cholesterol Ester Storage Disease (genetics), Cholesterol Ester Storage Disease (metabolism), Culture Media, Conditioned (pharmacology), Fibroblasts (metabolism), Humans, Lipoproteins (metabolism), Lipoproteins, HDL (metabolism), Mutation, Phospholipids (metabolism), Recombinant Proteins (metabolism), Skin (metabolism), Sterols (chemistry), Wolman Disease (genetics), Wolman Disease (metabolism).
- MESH :
- chemical , chemistry : Sterols.
- chemical , metabolism : ATP-Binding Cassette Transporters, Chloroquine, Cholesterol, Lipoproteins, Lipoproteins, HDL, Phospholipids, Recombinant Proteins.
- chemical , pharmacology : Culture Media, Conditioned.
- chemical : ATP Binding Cassette Transporter 1.
- genetics : Cholesterol Ester Storage Disease, Wolman Disease.
- metabolism : Cholesterol Ester Storage Disease, Fibroblasts, Skin, Wolman Disease.
- Humans, Mutation.
Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced α-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.
DOI: 10.1074/jbc.M111.274381
PubMed: 21757691
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pubmed:21757691Le document en format XML
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Bowden</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6</wicri:regionArea><wicri:noRegion>British Columbia V6Z 1Y6</wicri:noRegion></affiliation></author><author><name sortKey="Bilbey, Nicolas J" sort="Bilbey, Nicolas J" uniqKey="Bilbey N" first="Nicolas J" last="Bilbey">Nicolas J. Bilbey</name></author><author><name sortKey="Bilawchuk, Leanne M" sort="Bilawchuk, Leanne M" uniqKey="Bilawchuk L" first="Leanne M" last="Bilawchuk">Leanne M. Bilawchuk</name></author><author><name sortKey="Boadu, Emmanuel" sort="Boadu, Emmanuel" uniqKey="Boadu E" first="Emmanuel" last="Boadu">Emmanuel Boadu</name></author><author><name sortKey="Sidhu, Rohini" sort="Sidhu, Rohini" uniqKey="Sidhu R" first="Rohini" last="Sidhu">Rohini Sidhu</name></author><author><name sortKey="Ory, Daniel S" sort="Ory, Daniel S" uniqKey="Ory D" first="Daniel S" last="Ory">Daniel S. Ory</name></author><author><name sortKey="Du, Hong" sort="Du, Hong" uniqKey="Du H" first="Hong" last="Du">Hong Du</name></author><author><name sortKey="Chan, Teddy" sort="Chan, Teddy" uniqKey="Chan T" first="Teddy" last="Chan">Teddy Chan</name></author><author><name sortKey="Francis, Gordon A" sort="Francis, Gordon A" uniqKey="Francis G" first="Gordon A" last="Francis">Gordon A. Francis</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATP Binding Cassette Transporter 1</term><term>ATP-Binding Cassette Transporters (metabolism)</term><term>Chloroquine (metabolism)</term><term>Cholesterol (metabolism)</term><term>Cholesterol Ester Storage Disease (genetics)</term><term>Cholesterol Ester Storage Disease (metabolism)</term><term>Culture Media, Conditioned (pharmacology)</term><term>Fibroblasts (metabolism)</term><term>Humans</term><term>Lipoproteins (metabolism)</term><term>Lipoproteins, HDL (metabolism)</term><term>Mutation</term><term>Phospholipids (metabolism)</term><term>Recombinant Proteins (metabolism)</term><term>Skin (metabolism)</term><term>Sterols (chemistry)</term><term>Wolman Disease (genetics)</term><term>Wolman Disease (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Chloroquine (métabolisme)</term><term>Cholestérol (métabolisme)</term><term>Fibroblastes (métabolisme)</term><term>Humains</term><term>Lipoprotéines (métabolisme)</term><term>Lipoprotéines HDL (métabolisme)</term><term>Maladie de Wolman (génétique)</term><term>Maladie de Wolman (métabolisme)</term><term>Maladie de stockage des esters de cholestérol (génétique)</term><term>Maladie de stockage des esters de cholestérol (métabolisme)</term><term>Milieux de culture conditionnés (pharmacologie)</term><term>Mutation</term><term>Peau (métabolisme)</term><term>Phospholipides (métabolisme)</term><term>Protéines recombinantes (métabolisme)</term><term>Stérols ()</term><term>Transporteur-1 à cassette liant l'ATP</term><term>Transporteurs ABC (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Sterols</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>ATP-Binding Cassette Transporters</term><term>Chloroquine</term><term>Cholesterol</term><term>Lipoproteins</term><term>Lipoproteins, HDL</term><term>Phospholipids</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Culture Media, Conditioned</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>ATP Binding Cassette Transporter 1</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cholesterol Ester Storage Disease</term><term>Wolman Disease</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Maladie de Wolman</term><term>Maladie de stockage des esters de cholestérol</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cholesterol Ester Storage Disease</term><term>Fibroblasts</term><term>Skin</term><term>Wolman Disease</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Chloroquine</term><term>Cholestérol</term><term>Fibroblastes</term><term>Lipoprotéines</term><term>Lipoprotéines HDL</term><term>Maladie de Wolman</term><term>Maladie de stockage des esters de cholestérol</term><term>Peau</term><term>Phospholipides</term><term>Protéines recombinantes</term><term>Transporteurs ABC</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Milieux de culture conditionnés</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Mutation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Mutation</term><term>Stérols</term><term>Transporteur-1 à cassette liant l'ATP</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced α-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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