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Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr.
J LIPID RES
1760 - 1771.
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 nas 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 level 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.
|Title:||Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr|
|Open access status:||An open access publication|
|Keywords:||genetic variation, LPL inhibition, lipid binding, DMPC, apoE displacement, PROTEIN SECONDARY STRUCTURE, TRIGLYCERIDE-RICH LIPOPROTEINS, LOW-DENSITY-LIPOPROTEIN, LECITHIN-CHOLESTEROL-ACYLTRANSFERASE, AIV GENE-CLUSTER, AMINO-ACID-SEQUENCE, A-I, STRUCTURE PREDICTION, TRANSGENIC MICE, APO-CIII|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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