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Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages


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dc.contributorElizabeth Schwartz, ehs0009@auburn.eduen_US
dc.creatorZhu, Xuewei
dc.creatorLee, Ji-Young
dc.creatorTimmins, Jenelle M.
dc.creatorBrown, J. Mark
dc.creatorBoudyguina, Elena
dc.creatorMulya, Anny
dc.creatorGebre, Abraham K.
dc.creatorWillingham, Mark C.
dc.creatorHiltbold, Elizabeth M.
dc.creatorMishra, Nilamadhab
dc.date.accessioned2021-03-23T18:43:28Z
dc.date.available2021-03-23T18:43:28Z
dc.date.created2008-08
dc.identifier10.1074/jbc.M801408200en_US
dc.identifier.urihttp://www.jbc.org/content/283/34/22930en_US
dc.identifier.urihttps://aurora.auburn.edu/handle/11200/49983
dc.identifier.urihttp://dx.doi.org/10.35099/aurora-54
dc.description.abstractMacrophage-specific Abca1 knock-out (Abca1(-M/-M)) mice were generated to determine the role of macrophage ABCA1 expression in plasma lipoprotein concentrations and the innate immune response of macrophages. Plasma lipid and lipoprotein concentrations in chow-fed Abca1(-M/-M) and wild-type (WT) mice were indistinguishable. Compared with WT macrophages, Abca1(-M/-M) macrophages had a > 95% reduction in ABCA1 protein, failed to efflux lipid to apoA-I, and had a significant increase in free cholesterol (FC) and membrane lipid rafts without induction of endoplasmic reticulum stress. Lipopolysaccharide (LPS)-treated Abca1(-M/-M) macrophages exhibited enhanced expression of pro-inflammatory cytokines and increased activation of the NF-kappa B and MAPK pathways, which could be diminished by silencing MyD88 or by chemical inhibition of NF-kappa B or MAPK. In vivo LPS injection also resulted in a higher pro-inflammatory response in Abca1(-M/-M) mice compared with WT mice. Furthermore, cholesterol depletion of macrophages with methyl-beta-cyclodextrin normalized FC content between the two genotypes and their response to LPS; cholesterol repletion of macrophages resulted in increased cellular FC accumulation and enhanced cellular response to LPS. Our results suggest that macrophage ABCA1 expression may protect against atherosclerosis by facilitating the net removal of excess lipid from macrophages and dampening pro-inflammatory MyD88-dependent signaling pathways by reduction of cell membrane FC and lipid raft content.en_US
dc.formatPDFen_US
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCen_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.relation.ispartofseries0021-9258en_US
dc.rights© 2008. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectDENSITY-LIPOPROTEIN DEFICIENCYen_US
dc.subjectCASSETTE TRANSPORTER 1en_US
dc.subjectINDUCED INSULIN-RESISTANCEen_US
dc.subjectNECROSIS-FACTOR-ALPHAen_US
dc.subjectAPOLIPOPROTEIN-A-Ien_US
dc.subjectLIPID RAFTSen_US
dc.subjectTANGIER-DISEASEen_US
dc.subjectABCA1-DEFICIENT MACROPHAGESen_US
dc.subjectMEXICAN POPULATIONen_US
dc.subjectR230C VARIANTen_US
dc.titleIncreased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophagesen_US
dc.typeTexten_US
dc.type.genreJournal Article, Academic Journalen_US
dc.citation.volume283en_US
dc.citation.issue34en_US
dc.citation.spage22930en_US
dc.citation.epage22941en_US
dc.description.statusPublisheden_US
dc.description.peerreviewYesen_US

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