J. Lipid Res.
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A more recent version of this article appeared on April 1, 2004

Papers In Press, published online ahead of print January 16, 2004
J. Lipid Res., doi:10.1194/jlr.M300422-JLR200
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Submitted on October 7, 2003
Revised on December 22, 2003
Accepted on January 8, 2004

Pre-beta high density lipoprotein has two metabolic fates in human apolipoprotein A-I transgenic mice

Ji-Young Lee, Lorraine Lanningham-Foster, Elena Y. Boudyguina, Thomas L. Smith, Ellen R. Young, Perry L. Colvin, Michael J. Thomas, and John S. Parks

Department of Pathology, Wake Forest University, Winston-Salem, NC 27157

Corresponding Author: jparks{at}wfubmc.edu

We compared the in vivo metabolism of pre-beta high density lipoprotein (HDL) in human apoA-I transgenic mice (hA-I Tg) with that of lipid-free apoA-I (LFA-I) and small HDL. LpA-I, HDL particles isolated by anti-human apoA-I immunoaffinity chromatography, were purified from hA-I Tg mouse plasma and radiolabeled with 125I-tyramine cellobiose and fractionated into homogenous sized pre-beta and small LpA-I using FPLC. After injection, pre-beta LpA-I were removed from plasma more rapidly than LFA-I and small LpA-I doses (fractional catabolic rate; 7.7, 4.4, and 2.6 day-1, respectively). Pre-beta LpA-I and LFA-I were preferentially degraded by the kidney (3.2 and 1.6 day-1, respectively) compared to the liver (0.9 and 1.1 day-1), whereas small LpA-I showed a slight but significantly higher degradation by the liver compared to the kidney (0.7 vs. 0.6 day-1). Between 5-60 min after tracer injection into hA-I Tg mice, 99% of LFA-I in plasma was found associated with medium size HDL particles (8.6 nm), whereas only 37% of the pre-beta tracer remodeled to medium size HDL. Injection of pre-beta LpA-I doses into C57Bl/6 recipients resulted in a slower plasma decay compared to hA-I Tg recipients (3.3 vs. 7.7 day-1) and a greater proportion (>60%) of the pre-beta radiolabel that was associated with medium size HDL. Mass spectrometry analysis of LpA-I lipid extracts demonstrated that pre-beta LpA-I contained 1-4 molecules of phosphatidylcholine per molecule apoA-I, whereas LFA-I contained <1. We conclude that pre-beta LpA-I has two metabolic fates in vivo, rapid removal from plasma and catabolism by the kidney or remodeling to medium size HDL, which we hypothesize is determined by the amount of lipid associated with the pre-beta particle and the particle’s ability to bind to medium size HDL.


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