Inactivation of the LRP1 intracellular NPxYxxL motif in LDLR-deficient mice enhances postprandial dyslipidemia and atherosclerosis.
OBJECTIVE
The purpose of this study was to determine the significance of the intracellular NPxYxxL motif of LRP1 for the atheroprotective role of this multifunctional receptor.


RESULTS
LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with LDLR-deficient mice, a model for atherosclerosis. In this LDLR(-/-) background the mutated mice showed a more atherogenic lipoprotein profile, which was associated with a decreased clearance of postprandial lipids because of a compromised endocytosis rate and reduced lipase activity. On an atherogenic diet LRP1 mutant mice revealed a 50% increased development of atherosclerosis. This aggravation was accompanied by an increase in smooth muscle cell (SMC) and collagen content and apoptotic cells in the lesions. The mutation showed, however, a limited impact on basal PDGFR-beta expression and signaling and the antimigratory property of apoE on PDGF-BB-stimulated SMCs. Additionally, levels of LRP1 atherogenic ligands, like MMP2, t-PA, FVIII, and the inflammatory ligand TNF-alpha showed to be significantly elevated.


CONCLUSIONS
These findings demonstrate that the NPxYxxL motif is essential for the atheroprotective role of LRP1. This motif is relevant for normal control of lipid metabolism and of atherogenic and inflammatory ligands, but has no pronounced effect on regulating PDGF-BB/PDGFR-beta signaling in SMCs.
Gordts
Philip L S M
PL
Experimental Mouse Genetics, Center for Human Genetics, KU Leuven, Belgium.
Reekmans
Sara
S
Lauwers
Annick
A
Van Dongen
Amber
A
Verbeek
Leen
L
Roebroek
Anton J M
AJ
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077214:Becaplermin; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis; D055879:Gene Knock-In Techniques; D050356:Lipid Metabolism / Q000235:genetics; D008071:Lipoprotein Lipase / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D019518:Postprandial Period; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000077214:Becaplermin; D003094:Collagen; D020797:Receptor, Platelet-Derived Growth Factor beta; D008071:Lipoprotein Lipase