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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:560.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B-100 Production

John S. Millar; Cyrille Maugeais; Katsunori Ikewaki; Daniel M. Kolansky; P.Hugh R. Barrett; Elaine C. Budreck; Raymond C. Boston; Norio Tada; Seibu Mochizuki; Joep C. Defesche; James M. Wilson; Daniel J. Rader

From the Department of Medicine (J.S.M., C.M., D.M.K., E.C.B., J.M.W., D.J.R.), University of Pennsylvania, Philadelphia; the Division of Cardiology (K.I., S.M.), Department of Internal Medicine and the Department of General Medicine (N.T.), Kashiwa Hospital, Jikei University School of Medicine, Tokyo, Japan; the School of Medicine and Pharmacology (P.H.R.B.), University of Western Australia, Perth; the Biomathematics Unit (R.C.B.), University of Pennsylvania School of Veterinary Medicine, Kennett Square; and the Department of Vascular Medicine (J.C.D.), Academic Medical Center at the University of Amsterdam, the Netherlands.

Correspondence to John S. Millar, PhD, University of Pennsylvania, 644 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail jsmillar{at}mail.med.upenn.edu

Objective— We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans.

Methods and Results— Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. The FCRs of very-low-density lipoprotein 1 (VLDL1), VLDL2, intermediate-density lipoprotein (IDL), and LDL apoB were lower in FH than in controls, with the LDL apoB FCR being significantly lower (0.148±0.049 versus 0.499±0.099 pools · d^–1; P=0.008). Whereas receptor-defective FH patients had a total apoB PR similar to controls, receptor-null FH patients had a significantly greater total apoB PR than controls (35.97±10.51 versus 21.32±4.21 mg · kg^–1 · d^–1, respectively; P=0.02).

Conclusions— This first study of apoB metabolism in homozygous FH using endogenous labeling with stable isotopes demonstrates that the LDL receptor contributes significantly to the clearance of LDL from plasma but plays a lesser role in the clearance of larger apoB-containing lipoproteins. Furthermore, these data also indicate that absence of a LDL receptor in humans substantially influences the apoB PR in vivo.

Kinetic studies on apoB were conducted in genetically defined patients with homozygous FH. FH patients had significantly decreased clearance of LDL apoB. Receptor-null FH had a significantly increased apoB production. We conclude that the LDL receptor primarily mediates clearance of LDL apoB from plasma and can influence apoB production in vivo.

Key Words: cholesterol • familial hypercholesterolemia • VLDL • LDL • apoB

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