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Journal of Lipid Research, Vol. 45, 1459-1467, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

In vivo metabolism of LDL subfractions in patients with heterozygous FH on statin therapy

H. C. Geiss^*,, S. Bremer^*, P. H. R. Barrett, C. Otto^* and K. G. Parhofer^1,*

^* Department of Internal Medicine II, Grosshadern, University of Munich, Munich, Germany
Department of Internal Medicine I, University of Mainz, Mainz, Germany
Department of Medicine, University of Western Australia and the Western Australian Institute for Medical Research, Perth, Australia

¹ To whom correspondence should be addressed. e-mail: klaus.parhofer{at}med.uni-muenchen.de

LDL can be subfractionated into buoyant (1.020–1.029 g/ml^–1), intermediate (1.030–1.040 g/ml^–1), and dense (1.041–1.066 g/ml^–1) LDLs. We studied the rebound of these LDL-subfractions after LDL apheresis in seven patients with heterozygous familial hypercholesterolemia (FH) regularly treated by apheresis (58 ± 9 years, LDL-cholesterol = 342 ± 87 mg/dl^–1, triglycerides = 109 ± 39 mg/dl^–1) and high-dose statins. Apolipoprotein B (apoB) concentrations were measured in LDL subfractions immediately after and on days 1, 2, 3, 5, and 7 after apheresis. Compartmental models were developed to test three hypotheses: 1) that dense LDLs are derived from the delipidation of buoyant and intermediate LDLs (model A); 2) that dense LDLs are generated directly from LDL-precursors (model B); or 3) that a model combining both pathways (model C) is necessary to describe the metabolism of dense LDLs. In all models, it was assumed that apoB production and fractional catabolic rate (FCR) did not change with apheresis. Apheresis decreased buoyant, intermediate, and dense LDL-apoB by 60 ± 12%, 67 ± 5%, and 69 ± 11%, respectively. Models B and C, but not model A, described the rebound data. The model with the greatest biological plausibility (model C) was used to estimate metabolic parameters. FCR was 1.05 ± 0.86 d^–1, 0.48 ± 0.11 d^–1, and 0.69 ± 0.24 d^–1 for buoyant, intermediate, and dense LDLs, respectively. Dense LDL production was 17.3 ± 0.2 mg/kg^–1/d^–1, 58% of which was derived directly from LDL precursors (VLDL, IDL, or direct secretion), while 42% was derived from buoyant and intermediate LDLs.

Thus, our data indicate that in statin-treated patients with heterozygous FH dense LDLs originate from two sources. Whether this is also valid in other metabolic situations (with predominant small, dense LDLs) remains to be determined.

Abbreviations: AIC, Akaike information criterion; apoB, apolipoprotein B; DALI, direct absorption of lipoproteins; FCR, fractional catabolic rate; FH, familial hypercholesterolemia; HELP, heparin-induced extracorporeal LDL precipitation; IDL, intermediate density lipoprotein; PR, production rate

Supplementary key words low density lipoprotein subtypes • density gradient ultracentrifugation • familial hypercholesterolemia • small, dense low density lipoproteins • low density lipoprotein metabolism • rebound kinetics

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