Origin of apolipoprotein A-I polymorphism in plasma

The origin and the functional significance of apo-A-I polymorphism in man has been investigated. Together with proapo-A-I (identified as A-I₁ of the polymorphic series), four other isoforms are found in human plasma, namely A-I₂, A-I₃, A-I₄, AND A-I₅. A-I₃ is the 'mature' product of proapo A-I conversion in plasma. In this study we provide evidence that the other, more acidic, mature apo-A-I isoproteins are derived from A-I₃ by a stepwise deamidation process. This conclusion is based on the following observations. Incubation of A-I₃ or A-I₄, either free or associated with high density lipoprotein, produces a series of more acidic isoproteins corresponding to the sequence found in plasma. The conversion process fits in well with a first order reaction, and A-I₃ to A-I₄ conversion occurs virtually at the same rate as A-I₄ to A-I₅ conversion. A-I₃ and A-I₄ have the same NH₂- and C-terminal residues. Formation of apo-A-I acidic isoproteins is accompanied by liberation of ammonia. In order to investigate whether deamidation of apo-A-I results in the production of forms which have different catabolism, a series of turnover studies was carried out in normal volunteers. A-I₃ and A-I₄ residence times in plasma were, respectively, 3.50 ± 0.16 and 3.00 ± 0.10 days (mean ± S.E.; n = 3). Degradation rate of A-I₃ was 8.81 ± 0.69 mg/kg/day and that of A-I₄ was 1.66 ± 0.15 mg/kg/day (mean ± S.E.; n = 3). Conversion of A-I₃ to A-I₄ and A-I₄ to A-I₅ occured at the same rate in vivo as that observed in vitro. These results are consistent with the concept that A-I₃ is the precursor to the other mature apo-A-I isoforms in plasma. A-I₃ is the major isoform through which apo-A-I eliminated from plasma.