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

• Published in: PloS one Vol. 7; no. 6; p. e38330
• Main Authors: Gordts, Philip L S M, Bartelt, Alexander, Nilsson, Stefan K, Annaert, Wim, Christoffersen, Christina, Nielsen, Lars Bo, Heeren, Joerg, Roebroek, Anton J M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.06.2012; Public Library of Science (PLoS)
• Subjects: Amino Acid Motifs - genetics; Animals; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - deficiency; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - metabolism; Biochemistry; Biology; Blood cholesterol; Cell Fractionation; Cholesterol; Crosses, Genetic; Dyslipidemia; Dyslipidemias - metabolism; Endocytosis; Fluorescence; Gene Expression Regulation - physiology; Gene Knock-In Techniques; Genetics; Heparan sulfate; Hepatocytes; Hepatocytes - metabolism; Immunoblotting; In vivo methods and tests; Insulin; Laboratories; Lipid metabolism; Lipids; Lipoprotein (low density) receptors; Lipoproteins; Lipoproteins (low density); Low density lipoprotein; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Low density lipoprotein receptors; Low density lipoproteins; Medicine; Metabolic disorders; Metabolism; Mice; Mice, Transgenic; Mutation; Physiological aspects; Postprandial Period - physiology; Protein transport; Protein Transport - physiology; Protein turnover; Proteins; Recycling; Rodents; Statistics, Nonparametric; Studies; Translocation; Triglycerides; Triglycerides - blood; Veins & arteries; Belgium
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0038330

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. 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. 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.