Submitted on May 9, 2008
Revised on June 11, 2008
Accepted on June 24, 2008
Initial interaction of ApoA-I with ATP binding cassette transporter A1 (ABCA1) impacts in vivo metabolic fate of nascent HDL
Anny Mulya, Ji-Young Lee, Abraham K. Gebre, Elena Y. Boudyguina, Soon-Kyu Chung, Thomas L. Smith, Perry L. Colvin, Xian-Cheng Jiang, and John S. Parks
Pathology/Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Corresponding Author: jparks{at}wfubmc.edu
We investigated the in vivo metabolic fate of pre-
HDL particles in hA-I Tg mice. Pre- HDL tracers were assembled by incubation of 125I-tyramine cellobiose-labeled apoA-I with HEK293 cells expressing ATP binding cassette transporter A1 (ABCA1). Radiolabeled pre- HDL of increasing size (pre-1, 2, 3 and 4 HDL) were isolated by FPLC and injected into hA-I Tg recipient mice, after which plasma decay, in vivo remodeling and tissue uptake were monitored. Pre-2, 3, and 4 had similar plasma die-away rates, whereas pre-1 HDL was removed seven-fold more rapidly. Radiolabel recovered in liver and kidney 24h after tracer injection suggested increased (p<0.001) liver and decreased kidney catabolism as pre- HDL size increased. In plasma, pre-1 and 2 were rapidly (<5 min) remodeled into larger HDL, whereas pre-3 and 4 were remodeled into smaller HDL. Pre- 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- HDL particle size increases.
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