1. Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice
- Author
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Gordts, Philip LSM, Bartelt, Alexander, Nilsson, Stefan K, Annaert, Wim, Christoffersen, Christina, Nielsen, Lars Bo, Heeren, Joerg, and Roebroek, Anton JM
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Atherosclerosis ,Aging ,Cardiovascular ,Heart Disease ,2.1 Biological and endogenous factors ,Aetiology ,Amino Acid Motifs ,Animals ,Apolipoproteins E ,Cell Fractionation ,Crosses ,Genetic ,Dyslipidemias ,Fluorescence ,Gene Expression Regulation ,Gene Knock-In Techniques ,Hepatocytes ,Immunoblotting ,Low Density Lipoprotein Receptor-Related Protein-1 ,Mice ,Mice ,Transgenic ,Postprandial Period ,Protein Transport ,Statistics ,Nonparametric ,Triglycerides ,General Science & Technology - Abstract
ObjectiveDetermination 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.Methods and resultsLRP1 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.ConclusionThese 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.
- Published
- 2012