Linked Life Data

18948618

Source:http://linkedlifedata.com/resource/pubmed/id/18948618

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2008-11-25
pubmed:abstractText
Mutation in the EGFP domain of LDL receptor-related protein 6 (LRP6(R611C)) is associated with hypercholesterolemia and early-onset atherosclerosis, but the mechanism by which it causes disease is not known. Cholesterol uptake was examined in cells from LRP6(+/-) mice and LRP6(R611C) mutation carriers. Splenic B cells of LRP6(+/-) mice have significantly lower LRP6 expression and low-density lipoprotein (LDL) uptake than those of the wild-type littermates. Although similar levels of total LRP6 were found in lymphoblastoid cells (LCLs) of LRP6(R611C) mutation carriers and those of the unaffected family member, LDL uptake was significantly lower in the mutant cells. Mutant and wild-type receptors show similar affinities for apolipoprotein B at neutral pH. LRP6 colocalized with LDL and was coimmunoprecipitated with NPC1 (Niemann-Pick disease type C1), an endocytic regulator of LDL trafficking. However, the cellular localization of LRP6 in the mutant cells shifted from cell surface to late endosomes/lysosomes. Plasma membrane expression levels of LRP6(R611C) was lower compared to wild-type receptor and declined to a greater extent in LDL-rich medium. Further examinations revealed lower efficacy of apolipoprotein B dissociation from LRP6(R611C) compared to wild-type receptor at an acidic pH. These studies identify LRP6 as a receptor for LDL endocytosis and imply that R611C mutation results in reduced LRP6 membrane expression and decreased LDL clearance. Based on our findings, we conclude that the increased affinity of the mutant receptor for LDL in acidic pH leads to their impaired dissociation in late endosomes, which compromises their recycling to the plasma membrane.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
21
pubmed:volume
103
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1280-8
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:18948618-3T3 Cells, pubmed-meshheading:18948618-Amino Acid Substitution, pubmed-meshheading:18948618-Animals, pubmed-meshheading:18948618-Apolipoproteins B, pubmed-meshheading:18948618-B-Lymphocytes, pubmed-meshheading:18948618-Cell Line, pubmed-meshheading:18948618-Cell Membrane, pubmed-meshheading:18948618-Endosomes, pubmed-meshheading:18948618-Gene Expression Regulation, pubmed-meshheading:18948618-Green Fluorescent Proteins, pubmed-meshheading:18948618-Heterozygote Detection, pubmed-meshheading:18948618-Humans, pubmed-meshheading:18948618-Immunohistochemistry, pubmed-meshheading:18948618-LDL-Receptor Related Proteins, pubmed-meshheading:18948618-Lipoproteins, LDL, pubmed-meshheading:18948618-Low Density Lipoprotein Receptor-Related Protein-6, pubmed-meshheading:18948618-Lysosomes, pubmed-meshheading:18948618-Metabolic Clearance Rate, pubmed-meshheading:18948618-Mice, pubmed-meshheading:18948618-Mice, Knockout, pubmed-meshheading:18948618-Microscopy, Fluorescence, pubmed-meshheading:18948618-Mutation
pubmed:year
2008
pubmed:articleTitle
Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance.
pubmed:affiliation
Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn. 06520, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural