Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL

We investigated the in vivo metabolic fate of pre-beta HDL particles in human apolipoprotein A-I transgenic (hA-I-Tg) mice. Pre-beta HDL tracers were assembled by incubation of [I-125] tyramine cellobiose-labeled apolipoprotein A-I (apoA-I) with HEK293 cells expressing ABCA1. Radiolabeled pre-beta HDLs of increasing size (pre-beta 1, -2, -3, and -4 HDLs) were isolated by fast-protein liquid chromatography and injected into hA-I-Tg-recipient mice, after which plasma decay, in vivo remodeling, and tissue uptake were monitored. Pre-beta 2, -3, and -4 had similar plasma die-away rates, whereas pre-beta 1 HDL was removed 7-fold more rapidly. Radiolabel recovered in liver and kidney 24 h after tracer injection suggested increased (P < 0.001) liver and decreased kidney catabolism as pre-beta HDL size increased. In plasma, pre-beta 1 and -2 were rapidly (<5 min) remodeled into larger HDLs, whereas pre-beta 3 and -4 were remodeled into smaller HDLs. Pre-beta HDLs were similarly remodeled in vitro with control or LCAT-immunodepleted plasma, but not when incubated with phospholipid transfer protein knockout plasma. Our results suggest that initial interaction of apoA-I with ABCA1 imparts a unique conformation that partially determines the in vivo metabolic fate of apoA-I, resulting in increased liver and decreased kidney catabolism as pre-beta HDL particle size increases.