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dc.contributor.authorChoi, Seungbum
dc.contributor.authorAljakna, Alesksandra
dc.contributor.authorSrivastava, Ujala
dc.contributor.authorPeterson, Blake R.
dc.contributor.authorDeng, Bin
dc.contributor.authorPrat, Annik
dc.contributor.authorKorstanje, Ron
dc.date.accessioned2014-04-01T14:25:55Z
dc.date.available2014-04-01T14:25:55Z
dc.date.issued2013-07-24
dc.identifier.citationChoi, Seungbum, Aleksandra Aljakna, Ujala Srivastava, Blake R Peterson, Bin Deng, Annik Prat, and Ron Korstanje. 2013. “Decreased APOE-Containing HDL Subfractions and Cholesterol Efflux Capacity of Serum in Mice Lacking Pcsk9.” Lipids in Health and Disease 12:112. http://dx.doi.org/10.1186/1476-511X-12-112.
dc.identifier.urihttp://hdl.handle.net/1808/13390
dc.description.abstractBackground Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. Methods Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet. Results APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls. Conclusions In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.
dc.description.sponsorshipThis work was supported by HL081162, HL077796 and HL095668 from the National Heart, Lung and Blood Institute and by the Canadian Institutes of Health Research grants 82946 and 102741. The Proteomics Core Facility is supported by the Vermont Genetics Network through NIH grant 8P20GM103449 from the INBRE program of the National Institute of General Medical Sciences (NIGMS) and the National Center for Research Resources (NCRR). BRP thanks the NIH (CA83831) for financial support. AP was supported by the Canadian Institutes of Health Research grants 82946 and 102741.
dc.publisherStrangor
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/2.0
dc.subjectApolipoprotein e
dc.subjectAtherosclerotic fatty streak
dc.subjectLow-density lipoprotein receptor
dc.subjectMacrophage foam cell
dc.subjectProprotein convertase subtilisin/kexin type 9
dc.titleDecreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9.
dc.typeArticle
kusw.kuauthorPeterson, Blake R.
kusw.kudepartmentMedicinal Chemistry
kusw.oastatusfullparticipation
dc.identifier.doi10.1186/1476-511X-12-112
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.