Source:http://linkedlifedata.com/resource/pubmed/id/15576362
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
8
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pubmed:dateCreated |
2005-2-21
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pubmed:abstractText |
To identify the residues in the carboxyl-terminal region 260-299 of human apolipoprotein E (apoE) that contribute to hypertriglyceridemia, two sets of conserved, hydrophobic amino acids between residues 261 and 283 were mutated to alanines, and recombinant adenoviruses expressing these apoE mutants were generated. Adenovirus-mediated gene transfer of apoE4-mut1 (apoE4 (L261A, W264A, F265A, L268A, V269A)) in apoE-deficient mice (apoE(-/-)) corrected plasma cholesterol levels and did not cause hypertriglyceridemia. In contrast, gene transfer of apoE4-mut2 (apoE4 (W276A, L279A, V280A, V283A)) did not correct hypercholesterolemia and induced mild hypertriglyceridemia. ApoE-induced hyperlipidemia was corrected by co-infection with a recombinant adenovirus expressing human lipoprotein lipase. Both apoE4 mutants caused only a small increase in hepatic very low density lipoprotein-triglyceride secretion. Density gradient ultracentrifugation analysis of plasma and electron microscopy showed that wild-type apoE4 and apoE4-mut2 displaced apoA-I from the high density lipoprotein (HDL) region and promoted the formation of discoidal HDL, whereas the apoE4-mut1 did not displace apoA-I from HDL and promoted the formation of spherical HDL. The findings indicate that residues Leu-261, Trp-264, Phe-265, Leu-268, and Val-269 of apoE are responsible for hypertriglyceridemia and also interfere with the formation of HDL. Substitutions of these residues by alanine provide a recombinant apoE form with improved biological functions.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins E,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Lipoproteins, HDL,
http://linkedlifedata.com/resource/pubmed/chemical/Lipoproteins, VLDL,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Triglycerides,
http://linkedlifedata.com/resource/pubmed/chemical/very low density lipoprotein...
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
25
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6276-84
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:15576362-Animals,
pubmed-meshheading:15576362-Apolipoproteins E,
pubmed-meshheading:15576362-Cholesterol,
pubmed-meshheading:15576362-Female,
pubmed-meshheading:15576362-Humans,
pubmed-meshheading:15576362-Hypertriglyceridemia,
pubmed-meshheading:15576362-Lipoproteins, HDL,
pubmed-meshheading:15576362-Lipoproteins, VLDL,
pubmed-meshheading:15576362-Liver,
pubmed-meshheading:15576362-Mice,
pubmed-meshheading:15576362-Mice, Knockout,
pubmed-meshheading:15576362-Mutagenesis, Site-Directed,
pubmed-meshheading:15576362-Mutation, Missense,
pubmed-meshheading:15576362-Peptide Fragments,
pubmed-meshheading:15576362-Recombinant Proteins,
pubmed-meshheading:15576362-Transgenes,
pubmed-meshheading:15576362-Triglycerides
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pubmed:year |
2005
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pubmed:articleTitle |
Generation of a recombinant apolipoprotein E variant with improved biological functions: hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia.
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pubmed:affiliation |
Molecular Genetics, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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