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This article is available online at http://www.jlr.org hypercholesterolemia: relevance to atheroprotection. J. Lipid Res. 2011. 52: 2304-2313.Supplementary key words high density lipoprotein heterogeneity • HDL proteome • low density lipoprotein receptor mutations • premature atherosclerosis • apolipoprotein E Until now, premature atherosclerosis and coronary heart disease (CHD) typical of familial hypercholesterolemia (FH) have been primarily equated with marked elevation in circulating levels of atherogenic cholesterolrich LDL, resulting in attenuated LDL receptor activity due to LDL receptor gene mutations ( 1 ). Accumulating evidence suggests, however, that subnormal levels of atheroprotective HDL may equally contribute to accelerated atherogenesis in FH ( 2-7 ).The large Emerging Risk Factor Collaboration study fi rmly established that circulating HDL-cholesterol (HDL-C) levels less than approximately 1.2 mmol/l (50 mg/dl), which typically correspond to the 50th percentile in population studies, are independently and strongly associated with elevated coronary risk ( 3 ). For a one standard deviation decrement in HDL-C, CHD risk increased by 22% Abstract Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), refl ecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre-and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDLapheresis (>2 years). Apheresis lowered both plasma apoE ( ؊ 62%) and apoAI ( ؊ 16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ‫ف‬ 1:1 to 0.72:1 by apheresis, refl ecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ‫ف‬ 1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction ( ؊ 50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-␤ 1-HDL particle levels were subnormal following removal ( ؊ 53%) upon apheresis, suggesting that cellular cholesterol effl ux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance fl ux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix. -Orsoni, A