ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.
Identifieur interne : 002222 ( Main/Exploration ); précédent : 002221; suivant : 002223ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.
Auteurs : Braydon L. Burgess [Canada] ; Pamela F. Parkinson ; Margaret M. Racke ; Veronica Hirsch-Reinshagen ; Jianjia Fan ; Charmaine Wong ; Sophie Stukas ; Louise Theroux ; Jeniffer Y. Chan ; James Donkin ; Anna Wilkinson ; Danielle Balik ; Brian Christie ; Judes Poirier ; Dieter Lütjohann ; Ronald B. Demattos ; Cheryl L. WellingtonSource :
- Journal of lipid research [ 0022-2275 ] ; 2008.
English descriptors
- KwdEn :
- ATP Binding Cassette Transporter, Sub-Family G, Member 1, ATP-Binding Cassette Transporters (physiology), Amyloid beta-Protein Precursor (metabolism), Animals, Apolipoproteins E (metabolism), Base Sequence, Biological Transport, Brain (metabolism), Cells, Cultured, Cholesterol (biosynthesis), DNA Primers, DNA-Binding Proteins (metabolism), Lipoproteins (physiology), Liver X Receptors, Mice, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear (metabolism), Reverse Transcriptase Polymerase Chain Reaction.
- MESH :
- chemical , biosynthesis : Cholesterol.
- chemical , metabolism : Amyloid beta-Protein Precursor, Apolipoproteins E, DNA-Binding Proteins, Receptors, Cytoplasmic and Nuclear.
- chemical , physiology : Lipoproteins.
- chemical : ATP Binding Cassette Transporter, Sub-Family G, Member 1, DNA Primers, Liver X Receptors, Orphan Nuclear Receptors.
- metabolism : Brain.
- physiology : ATP-Binding Cassette Transporters.
- Animals, Base Sequence, Biological Transport, Cells, Cultured, Mice, Reverse Transcriptase Polymerase Chain Reaction.
Abstract
Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Abeta production. To clarify the in vivo roles of ABCG1 in Abeta metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Abeta, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Abeta levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Abeta metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.
DOI: 10.1194/jlr.M700481-JLR200
PubMed: 18314463
Affiliations:
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Parkinson</name></author><author><name sortKey="Racke, Margaret M" sort="Racke, Margaret M" uniqKey="Racke M" first="Margaret M" last="Racke">Margaret M. Racke</name></author><author><name sortKey="Hirsch Reinshagen, Veronica" sort="Hirsch Reinshagen, Veronica" uniqKey="Hirsch Reinshagen V" first="Veronica" last="Hirsch-Reinshagen">Veronica Hirsch-Reinshagen</name></author><author><name sortKey="Fan, Jianjia" sort="Fan, Jianjia" uniqKey="Fan J" first="Jianjia" last="Fan">Jianjia Fan</name></author><author><name sortKey="Wong, Charmaine" sort="Wong, Charmaine" uniqKey="Wong C" first="Charmaine" last="Wong">Charmaine Wong</name></author><author><name sortKey="Stukas, Sophie" sort="Stukas, Sophie" uniqKey="Stukas S" first="Sophie" last="Stukas">Sophie Stukas</name></author><author><name sortKey="Theroux, Louise" sort="Theroux, Louise" uniqKey="Theroux L" first="Louise" last="Theroux">Louise Theroux</name></author><author><name sortKey="Chan, Jeniffer Y" sort="Chan, Jeniffer Y" uniqKey="Chan J" first="Jeniffer Y" last="Chan">Jeniffer Y. 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Burgess</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver</wicri:regionArea><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Parkinson, Pamela F" sort="Parkinson, Pamela F" uniqKey="Parkinson P" first="Pamela F" last="Parkinson">Pamela F. Parkinson</name></author><author><name sortKey="Racke, Margaret M" sort="Racke, Margaret M" uniqKey="Racke M" first="Margaret M" last="Racke">Margaret M. Racke</name></author><author><name sortKey="Hirsch Reinshagen, Veronica" sort="Hirsch Reinshagen, Veronica" uniqKey="Hirsch Reinshagen V" first="Veronica" last="Hirsch-Reinshagen">Veronica Hirsch-Reinshagen</name></author><author><name sortKey="Fan, Jianjia" sort="Fan, Jianjia" uniqKey="Fan J" first="Jianjia" last="Fan">Jianjia Fan</name></author><author><name sortKey="Wong, Charmaine" sort="Wong, Charmaine" uniqKey="Wong C" first="Charmaine" last="Wong">Charmaine Wong</name></author><author><name sortKey="Stukas, Sophie" sort="Stukas, Sophie" uniqKey="Stukas S" first="Sophie" last="Stukas">Sophie Stukas</name></author><author><name sortKey="Theroux, Louise" sort="Theroux, Louise" uniqKey="Theroux L" first="Louise" last="Theroux">Louise Theroux</name></author><author><name sortKey="Chan, Jeniffer Y" sort="Chan, Jeniffer Y" uniqKey="Chan J" first="Jeniffer Y" last="Chan">Jeniffer Y. Chan</name></author><author><name sortKey="Donkin, James" sort="Donkin, James" uniqKey="Donkin J" first="James" last="Donkin">James Donkin</name></author><author><name sortKey="Wilkinson, Anna" sort="Wilkinson, Anna" uniqKey="Wilkinson A" first="Anna" last="Wilkinson">Anna Wilkinson</name></author><author><name sortKey="Balik, Danielle" sort="Balik, Danielle" uniqKey="Balik D" first="Danielle" last="Balik">Danielle Balik</name></author><author><name sortKey="Christie, Brian" sort="Christie, Brian" uniqKey="Christie B" first="Brian" last="Christie">Brian Christie</name></author><author><name sortKey="Poirier, Judes" sort="Poirier, Judes" uniqKey="Poirier J" first="Judes" last="Poirier">Judes Poirier</name></author><author><name sortKey="Lutjohann, Dieter" sort="Lutjohann, Dieter" uniqKey="Lutjohann D" first="Dieter" last="Lütjohann">Dieter Lütjohann</name></author><author><name sortKey="Demattos, Ronald B" sort="Demattos, Ronald B" uniqKey="Demattos R" first="Ronald B" last="Demattos">Ronald B. Demattos</name></author><author><name sortKey="Wellington, Cheryl L" sort="Wellington, Cheryl L" uniqKey="Wellington C" first="Cheryl L" last="Wellington">Cheryl L. Wellington</name></author></analytic><series><title level="j">Journal of lipid research</title><idno type="ISSN">0022-2275</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATP Binding Cassette Transporter, Sub-Family G, Member 1</term><term>ATP-Binding Cassette Transporters (physiology)</term><term>Amyloid beta-Protein Precursor (metabolism)</term><term>Animals</term><term>Apolipoproteins E (metabolism)</term><term>Base Sequence</term><term>Biological Transport</term><term>Brain (metabolism)</term><term>Cells, Cultured</term><term>Cholesterol (biosynthesis)</term><term>DNA Primers</term><term>DNA-Binding Proteins (metabolism)</term><term>Lipoproteins (physiology)</term><term>Liver X Receptors</term><term>Mice</term><term>Orphan Nuclear Receptors</term><term>Receptors, Cytoplasmic and Nuclear (metabolism)</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Cholesterol</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Amyloid beta-Protein Precursor</term><term>Apolipoproteins E</term><term>DNA-Binding Proteins</term><term>Receptors, Cytoplasmic and Nuclear</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Lipoproteins</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>ATP Binding Cassette Transporter, Sub-Family G, Member 1</term><term>DNA Primers</term><term>Liver X Receptors</term><term>Orphan Nuclear Receptors</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>ATP-Binding Cassette Transporters</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Biological Transport</term><term>Cells, Cultured</term><term>Mice</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Abeta production. To clarify the in vivo roles of ABCG1 in Abeta metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Abeta, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Abeta levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Abeta metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Balik, Danielle" sort="Balik, Danielle" uniqKey="Balik D" first="Danielle" last="Balik">Danielle Balik</name><name sortKey="Chan, Jeniffer Y" sort="Chan, Jeniffer Y" uniqKey="Chan J" first="Jeniffer Y" last="Chan">Jeniffer Y. Chan</name><name sortKey="Christie, Brian" sort="Christie, Brian" uniqKey="Christie B" first="Brian" last="Christie">Brian Christie</name><name sortKey="Demattos, Ronald B" sort="Demattos, Ronald B" uniqKey="Demattos R" first="Ronald B" last="Demattos">Ronald B. Demattos</name><name sortKey="Donkin, James" sort="Donkin, James" uniqKey="Donkin J" first="James" last="Donkin">James Donkin</name><name sortKey="Fan, Jianjia" sort="Fan, Jianjia" uniqKey="Fan J" first="Jianjia" last="Fan">Jianjia Fan</name><name sortKey="Hirsch Reinshagen, Veronica" sort="Hirsch Reinshagen, Veronica" uniqKey="Hirsch Reinshagen V" first="Veronica" last="Hirsch-Reinshagen">Veronica Hirsch-Reinshagen</name><name sortKey="Lutjohann, Dieter" sort="Lutjohann, Dieter" uniqKey="Lutjohann D" first="Dieter" last="Lütjohann">Dieter Lütjohann</name><name sortKey="Parkinson, Pamela F" sort="Parkinson, Pamela F" uniqKey="Parkinson P" first="Pamela F" last="Parkinson">Pamela F. Parkinson</name><name sortKey="Poirier, Judes" sort="Poirier, Judes" uniqKey="Poirier J" first="Judes" last="Poirier">Judes Poirier</name><name sortKey="Racke, Margaret M" sort="Racke, Margaret M" uniqKey="Racke M" first="Margaret M" last="Racke">Margaret M. Racke</name><name sortKey="Stukas, Sophie" sort="Stukas, Sophie" uniqKey="Stukas S" first="Sophie" last="Stukas">Sophie Stukas</name><name sortKey="Theroux, Louise" sort="Theroux, Louise" uniqKey="Theroux L" first="Louise" last="Theroux">Louise Theroux</name><name sortKey="Wellington, Cheryl L" sort="Wellington, Cheryl L" uniqKey="Wellington C" first="Cheryl L" last="Wellington">Cheryl L. Wellington</name><name sortKey="Wilkinson, Anna" sort="Wilkinson, Anna" uniqKey="Wilkinson A" first="Anna" last="Wilkinson">Anna Wilkinson</name><name sortKey="Wong, Charmaine" sort="Wong, Charmaine" uniqKey="Wong C" first="Charmaine" last="Wong">Charmaine Wong</name></noCountry><country name="Canada"><noRegion><name sortKey="Burgess, Braydon L" sort="Burgess, Braydon L" uniqKey="Burgess B" first="Braydon L" last="Burgess">Braydon L. Burgess</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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