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


RESULTS
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.


CONCLUSIONS
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.
Laboratory for Experimental Mouse Genetics, Center for Human Genetics, KU Leuven, Leuven, Belgium.
Philip L S M
PL
Gordts
Alexander
A
Bartelt
Stefan K
SK
Nilsson
Wim
W
Annaert
Christina
C
Christoffersen
Lars Bo
LB
Nielsen
Joerg
J
Heeren
Anton J M
AJ
Roebroek
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism*; D002458:Cell Fractionation; D003433:Crosses, Genetic; D050171:Dyslipidemias / Q000378:metabolism*; D005453:Fluorescence; D005786:Gene Expression Regulation / Q000502:physiology*; D055879:Gene Knock-In Techniques; D022781:Hepatocytes / Q000378:metabolism; D015151:Immunoblotting; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019518:Postprandial Period / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D018709:Statistics, Nonparametric; D014280:Triglycerides / Q000097:blood
D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D014280:Triglycerides