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J Lipid Res ; 41(11): 1760-71, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11060345

RESUMO

We have identified a G-to-A transition in exon 3 of the APOC3 gene resulting in a novel Ala23Thr apolipoprotein (apo) C-III variant, associated with apoC-III deficiency in three unrelated Yucatan Indians. The Ala23Thr substitution modifies the hydrophobic/hydrophilic repartition of the helical N-terminal peptide and hence could disturb the lipid association. In vitro expression in Escherichia coli of wild-type and mutant apoC-III enabled the characterization of the variant. Compared with wild-type apoC-III-Ala23, the mutant apoC-III-Thr23 showed reduced affinity for dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles with higher amounts of free apoC-III. Displacement of apoE from discoidal apoE:dipalmitoylphosphatidycholine (DPPC) complex by apoC-III-Thr23 was comparable to wild type but the less efficient binding of the apoC-III-Thr23 to the discoidal complex resulted in a higher apoE/apoC-III (mol/mol) ratio (34%) than with wild-type/apoE:DPPC mixtures. The inhibition of lipoprotein lipase (LPL) by apoC-III-Thr23 was comparable to that of wild type, and therefore effects on LPL activity could not explain the lower triglyceride (Tg) levels in Thr-23 carriers. Thus, these in vitro results suggest that in vivo the less efficient lipid binding of apoC-III-Thr23 might lead to a faster catabolism of free apoC-III, reflected in the reduced plasma apoC-III levels identified in Thr-23 carriers, and poorer competition with apoE, which might enhance clearance of Tg-rich lipoproteins and lower plasma Tg levels seen in Thr-23 carriers.


Assuntos
Apolipoproteínas C/genética , Metabolismo dos Lipídeos , Lipase Lipoproteica/antagonistas & inibidores , Mutação , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Sequência de Aminoácidos , Apolipoproteína C-III , Apolipoproteínas C/deficiência , Apolipoproteínas C/metabolismo , Apolipoproteínas E/metabolismo , América Central , Fenômenos Químicos , Físico-Química , Análise Mutacional de DNA , Dimiristoilfosfatidilcolina/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Indígenas Centro-Americanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Proteínas Recombinantes/farmacologia
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