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Abstract
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.—Liu, H., C. Labeur, C-F. Xu, R. Ferrell, L. Lins, R. Brasseur, M. Rosseneu, K. M. Weiss, S. E. Humphries, and P. J. Talmud. Characterization of the lipid-binding properties and lipoprotein lipase inhibition of a novel apolipoprotein C-III variant Ala23Thr. J. Lipid Res. 2000. 41: 1760–1771.
Highlights
We have identified a G-to-A transition in exon 3 of the APOC3 gene resulting in a novel Ala23Thr apolipoprotein C-III variant, associated with apoC-III deficiency in three unrelated Yucatan Indians
ApoC-III acts as a marker of Tg-rich lipoprotein (TGRL) metabolism and the apoC-III high density lipoprotein (HDL):very low density lipoprotein (VLDL) ratio has been found to be negatively associated with the progression of atherosclerosis in a number of studies [7, 8]
The nucleotide sequences of the APOC3 gene including the 5Ј flanking region, all exons, and the 3Ј flanking region (Ϫ345 to 3545), were examined in four DNA samples from Mayan Indians with plasma apoC-III levels of 1.6, 1.9, 8.4, and 18.4 mg/dl, respectively, using polymerase chain reaction (PCR) and direct sequencing
Summary
The lowland Mayan Indians inhabit the Yucatan peninsula and other parts of Central America. The 192 Caucasian control males (aged 51 –60 years), free from CAD, were recruited from a general practitioner practice in Camberley, south London [21]
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