Proapolipoprotein A-I conversion kinetics in vivo in human and in rat

We have determined the turnover rates for proapolipoprotein A-I (proapoA-I) and mature apolipoprotein A-I (apoA-I) in vivo in human and in rat. For the human study, high density lipoprotein (HDL)-associated 125I-labeled proapoA-I (A-I isoform 1) and 131I-labeled mature apoA-I (A-I isoforms 3, 4, and 5) were injected simultaneously into two normal volunteers. Blood samples were obtained serially and HDL proapoA-I and mature apoA-I were separated by isoelectrofocusing for the determination of the associated radioactivity. Residence times of proapoA-I and mature apoA-I were 0.13 and 3.9 days and production rates were 9.0 and 9.3 mg/kg per day, respectively. Analysis of the specific activity curves suggested a complete proapoA-I to mature apoA-I precursor-product relationship. Proprotein conversion was virtually completed in 24 hr. For the rat study, HDL- and lymph chylomicron- (flotation constant Sf greater than 400 S) associated 125I-labeled proapoA-I and 131I-mature apoA-I were injected into fasted rats. Residence times of proapoA-I and mature apoA-I injected in association with HDL were 0.13 and 0.28 day, respectively, and for injection associated with chylomicrons the residence times were 0.08 and 0.26 day. When associated with chylomicrons, proapoA-I was converted more efficiently to the mature form. As in the human study, the results demonstrated a complete proapoA-I to mature apoA-I precursor-product relationship. Our data are consistent with the concepts that (i) conversion to mature apoA-I is the major proapoA-I catabolic fate in plasma; (ii) mature apoA-I is conceivably derived solely from proapoA-I in plasma and proapoA-I is the major apoA-I form secreted in vivo; and (iii) a putative proapoA-I-chylomicron complex is the preferred substrate for the apoA-I propeptidase.