Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.

<h4>Objective</h4>Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.<h4>Methods and results</h4>LRP1 knock-in mice carrying an inactivating muta...

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Autores principales:	Philip L S M Gordts, Alexander Bartelt, Stefan K Nilsson, Wim Annaert, Christina Christoffersen, Lars Bo Nielsen, Joerg Heeren, Anton J M Roebroek
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/964b5f858a5f4d03bd8bfaeec9dd7143
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spelling	oai:doaj.org-article:964b5f858a5f4d03bd8bfaeec9dd71432021-11-18T07:16:12ZImpaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.1932-620310.1371/journal.pone.0038330https://doaj.org/article/964b5f858a5f4d03bd8bfaeec9dd71432012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22701627/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Objective</h4>Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.<h4>Methods and results</h4>LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels.<h4>Conclusion</h4>These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.Philip L S M GordtsAlexander BarteltStefan K NilssonWim AnnaertChristina ChristoffersenLars Bo NielsenJoerg HeerenAnton J M RoebroekPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e38330 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Philip L S M Gordts Alexander Bartelt Stefan K Nilsson Wim Annaert Christina Christoffersen Lars Bo Nielsen Joerg Heeren Anton J M Roebroek Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
description	<h4>Objective</h4>Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.<h4>Methods and results</h4>LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels.<h4>Conclusion</h4>These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.
format	article
author	Philip L S M Gordts Alexander Bartelt Stefan K Nilsson Wim Annaert Christina Christoffersen Lars Bo Nielsen Joerg Heeren Anton J M Roebroek
author_facet	Philip L S M Gordts Alexander Bartelt Stefan K Nilsson Wim Annaert Christina Christoffersen Lars Bo Nielsen Joerg Heeren Anton J M Roebroek
author_sort	Philip L S M Gordts
title	Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
title_short	Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
title_full	Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
title_fullStr	Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
title_full_unstemmed	Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.
title_sort	impaired ldl receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoe-deficient mice.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/964b5f858a5f4d03bd8bfaeec9dd7143
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Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice.

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