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

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J. Lipid Res., doi:10.1194/jlr.M300523-JLR200
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Submitted on December 23, 2003
Revised on May 25, 2004
Accepted on May 28, 2004

In vivo metabolism of LDL-subfractions in patients with heterozygous familial hypercholesterolemia on statin therapy: rebound analysis of LDL subfractions following LDL-apheresis

H. Christian Geiss, Sabine Bremer, P. Hugh R. Barrett, Carsten Otto, and Klaus G. Parhofer

Medical Dpt. II, Grosshadern, University Munich, Munich 81377

Corresponding Author: Klaus.Parhofer{at}med.uni-muenchen.de

LDL can be subfractionated by density gradient ultracentrifugation into buoyant (1.020-1.029 g*mL-1), intermediate (1.030-1.040 g*mL-1), and dense LDL (1.041-1.066 g*mL-1). We studied the rebound of these LDL-subfractions following LDL-apheresis in 7 patients with heterozygous familial hypercholesterolemia regularly treated by apheresis (58±9 years, LDL-cholesterol 342±87 mg*dL-1, triglycerides 109±39 mg*dL-1) and high dose statins. Apo-B 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 LDL is derived from the delipidation of buoyant and intermediate LDL (model A), (2) that dense LDL is 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 LDL. In all models it was assumed that apoB production and fractional catabolic rate did not change with apheresis. Apheresis decreased apoB in buoyant LDL from 11.4±3.1 to 4.5±1.6 mg*dL-1 (-60±12%), in intermediate LDL from 60.3±7.2 to 20.0±2.7 mg*dL-1 (-67±5%), and in dense LDL from 64.8±18.9 to 19.2±5.9 mg*dL-1 (-69±11%). Models B and C, but not model A described the rebound data. Using the model with the greatest biological plausibility (model C) apoB fractional catabolic rates were estimated to be 1.05±0.86 d-1, 0.48±0.11 d-1, and 0.69±0.24 d-1 for buoyant, intermediate, and dense LDL-subfractions, respectively. The production rate of dense LDL was 17.3±0.2 mg*kg-1*d-1, 58% of which was derived directly from LDL precursors (VLDL, IDL or apoB directly secreted into plasma), while 42% was derived from buoyant and intermediate LDL. Thus, our data indicate that in statin treated patients with heterozygous familial hypercholesterolemia dense LDL originate from 2 sources, directly from LDL-precursors and from less dense LDL subfractions. Whether this model is also valid in other metabolic situations (with predominant dense LDL) remains to be determined.


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