J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M500179-JLR200 on July 16, 2005

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Journal of Lipid Research, Vol. 46, 2233-2245, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

HDLs in apoA-I transgenic Abca1 knockout mice are remodeled normally in plasma but are hypercatabolized by the kidney

Ji-Young Lee1,*, Jenelle M. Timmins1,*, Anny Mulya*, Thomas L. Smith{dagger}, Yiwen Zhu§, Edward M. Rubin§, Jeffrey W. Chisholm**, Perry L. Colvin{dagger}{dagger} and John S. Parks2,*

* Departments of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
{dagger} Orthopedic Surgery, Wake Forest University School of Medicine, Winston-Salem, NC 27157
§ Department of Genome Sciences, E. O. Lawrence Berkeley National Laboratory, Berkeley, CA 94720
** Discovery Research, CV Therapeutics, Inc., Palo Alto, CA, 94304
{dagger}{dagger} Division of Gerontology, University of Maryland School of Medicine, and Geriatrics Research, Education, and Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201

Published, JLR Papers in Press, July 16, 2005. DOI 10.1194/jlr.M500179-JLR200

1 J-Y. Lee and J. M. Timmins contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: jparks{at}wfubmc.edu

Patients homozygous for Tangier disease have a near absence of plasma HDL as a result of mutations in ABCA1 and hypercatabolize normal HDL particles. To determine the relationship between ABCA1 expression and HDL catabolism, we investigated intravascular remodeling, plasma clearance, and organ-specific uptake of HDL in mice expressing the human apolipoprotein A-I (apoA-I) transgene in the Abca1 knockout background. Small HDL particles (7.5 nm), radiolabeled with 125I-tyramine cellobiose, were injected into recipient mice to quantify plasma turnover and the organ uptake of tracer. Small HDL tracer was remodeled to 8.2 nm diameter particles within 5 min in human apolipoprotein A-I transgenic (hA-ITg) mice (control) and knockout mice. Decay of tracer from plasma was 1.6-fold more rapid in knockout mice (P < 0.05) and kidney uptake was twice that of controls, with no difference in liver uptake. We also observed 2-fold greater hepatic expression of ABCA1 protein in hA-ITg mice compared with nontransgenic mice, suggesting that overexpression of human apoA-I stabilized hepatic ABCA1 protein in vivo.

We conclude that ABCA1 is not required for in vivo remodeling of small HDLs to larger HDL subfractions and that the hypercatabolism of normal HDL particles in knockout mice is attributable to a selective catabolism of HDL apoA-I by the kidney.

Abbreviations: apoA-I, apolipoprotein A-I; CE, cholesteryl ester; EC, esterified cholesterol; FC, free cholesterol; FCR, fractional catabolic rate; FPLC, fast-protein liquid chromatography; hA-ITg, human apolipoprotein A-I transgenic; PL, phospholipid; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B type I; TC, tyramine cellobiose; WHAM, Wisconsin Hypoalpha Mutant

Supplementary key words apolipoprotein A-I • ATP binding cassette transporter A1 • high density lipoprotein


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