In vivo studies of HDL assembly and metabolism using adenovirus-mediated transfer of apoA-I mutants in apoA-I-deficient mice

被引:20
作者
Reardon, CA
Kan, HY
Cabana, V
Blachowicz, L
Lukens, JR
Wu, QZ
Liadaki, K
Getz, GS
Zannis, VI
机构
[1] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[2] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Mol Genet Sect, Boston, MA 02118 USA
关键词
D O I
10.1021/bi011451e
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have used adenovirus-mediated gene transfer in apoA-I-deficient (A-I-/-) mice to probe the in vivo assembly and metabolism of HDL using apoA-I variants, focusing primarily on the role of the C-terminal 32 amino acids (helices 9-10). Lipid, lipoprotein, and apoA-I analyses showed that plasma levels of apoA-I and HDL of the mutants were 40-88% lower than that of wild type (WT) human apoA-I despite comparable levels of expression in the liver. WT apoA-I and mutant 1 (P165A, E172A) formed spherical particles with the size and density of HDL2 and HDL3. Mutant 2 (E234A, E235A, K238A, K239A) generated spherical particles with density between HDL2 and HDL3. Mutant 3 (L211V, L214V, L218V, L219V) and mutant 4 (L222K, F225K, F229K), which have substitutions of hydrophobic residues in the C-terminus, generated discoidal HDL particles indicating a defect in their conversion to mature spherical HDL. Significant amounts of mutant 4 and mutant 5 (truncated at residue 219) were found in the lipid poor fractions after ultracentrifugation of the plasma (18 and 35%, respectively, of total apoA-I). These findings suggest that hydrophobic residues in and/or between helices 9 and 10 are important for the maturation of HDL in vivo.
引用
收藏
页码:13670 / 13680
页数:11
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