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Journal of Lipid Research, Vol. 45, 1302-1311, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Abnormal in vivo metabolism of apoB-containing lipoproteins in human apoE deficiency

Katsunori Ikewaki^1,*,, William Cain, Fairwell Thomas^*, Robert Shamburek^*, Loren A. Zech^*, David Usher, H. Bryan Brewer, Jr.^* and Daniel J. Rader^*,**

^* Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
School of Life and Health Sciences, University of Delaware, Newark, DE 19716
Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, Japan 105-8461
^** University of Pennsylvania Medical Center, 654 BREII/III 421 Curie Boulevard, Philadelphia, PA 19104-6160

¹ To whom correspondence should be addressed. e-mail: kikewaki{at}jikei.ac.jp

The present study was undertaken to elucidate the metabolic basis for the increased remnants and lipoprotein(a) [Lp(a)] and decreased LDL apolipoprotein B (apoB) levels in human apoE deficiency. A primed constant infusion of ¹³C₆-phenylalanine was administered to a homozygous apoE-deficient subject. apoB-100 and apoB-48 were isolated, and tracer enrichments were determined by gas chromatography-mass spectrometry, then kinetic parameters were calculated by multicompartmental modeling. In the apoE-deficient subject, fractional catabolic rates (FCRs) of apoB-100 in VLDL and intermediate density lipoprotein and apoB-48 in VLDL were 3x, 12x, and 12x slower than those of controls. On the other hand, the LDL apoB-100 FCR was increased by 2.6x. The production rate of VLDL apoB-100 was decreased by 45%. In the Lp(a) kinetic study, two types of Lp(a) were isolated from plasma with apoE deficiency: buoyant and normal Lp(a). ¹²⁵I-buoyant Lp(a) was catabolized at a slower rate in the patient. However, ¹²⁵I-buoyant Lp(a) was catabolized at twice as fast as ¹³¹I-normal Lp(a) in the control subjects.

In summary, apoE deficiency results in: 1) a markedly impaired catabolism of VLDL/chylomicron and their remnants due to lack of direct removal and impaired lipolysis; 2) an increased rate of catabolism of LDL apoB-100, likely due to upregulation of LDL receptor activity; 3) reduced VLDL apoB production; and 4) a delayed catabolism of a portion of Lp(a).

Abbreviations: apoE, apolipoprotein E; BMI, body mass index; FCR, fractional catabolic rate; GC-MS, gas chromatography-mass spectrometry; HDL-C, HDL cholesterol; IDL, intermediate density lipoprotein; Lp(a), lipoprotein(a); LRP, LDL receptor-related protein; PR, production rate; RT, residence time; TC, total cholesterol; TG, triglyceride; T/T, tracer/tracee

Supplementary key words apolipoprotein B • apolipoprotein E • kinetics • lipoprotein(a) • stable isotopes

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