KINETIC EVIDENCE FOR BOTH A FAST AND A SLOW SECRETORY PATHWAY FOR APOLIPOPROTEIN-A-I IN HUMANS

The kinetics of apolipoproteins A-I and A-II were examined in human su bjects using leucine tracers administered intravenously. High density lipoproteins were separated and apoA-I and A-II were isolated. The spe cific activity or enrichment data for these apolipoprotein were analyz ed by mathematical compartmental modeling. In 11 of 14 subjects studie d with a bolus-injected [H-3]leucine tracer, in 3 subjects studied sim ilarly with [H-3]leucine, and in one subject studied by primed dose, c onstant infusion of [H-3]leucine, a rapidly turning-over apoA-I fracti on was resolved. A similar component was observed in 7 of 10 studies o f apoA-II. The apoA-I data were analyzed using a compartmental model ( Zech, L. A. et al. 1983. J. Lipid Res. 24: 60-71) modified to incorpor ate plasma leucine as a precursor for apoprotein synthesis. The data p ermitted resolution of two apoA-I pools, one, C(2), turned-over with a residence time of less than 1 day, the other, C(1), a slowly turning- over pool, appeared in plasma after a delay of less than half a day. C (1) comprised the predominant mass of apoA-I and was also the primary determinant of the residence time of apoA-I. Although the mass of the fast pool, C(2), was considerably less than that of C(1), because of i ts rapid turnover, the quantities of apoA-I transported through this f ast pathway were 2- to 4-fold greater. These kinetic studies indicate that apoA-I is secreted into bath fast and slowly turning-over plasma pools. The latter is predominantly measured with radioiodinated apoA-I tracers. The data can be analyzed by postulating either separate inpu t pathways to each of the pools or by assuming the fast pool is the pr ecursor to the slow pool. Thus, apoA-I could be initially secreted as a family of particles that are rapidly cleared from plasma, and a port ion of this apoprotein then reappears in a slowly turning-over pool th at constitutes the major mass of apoA-I. The physiologic identity of t hese kinetically distinct apoA-I species is unknown; however, the fast pool of apoA-I demonstrated in these studies is strikingly similar to that seen in subjects with Tangier disease who lack the slow pool.