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(Circulation. 2003;107:1366.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Cellular Phospholipid and Cholesterol Efflux in High-Density Lipoprotein Deficiency

Michel Marcil, PhD; Rachel Bissonnette, MSc; Jérôme Vincent, DEA; Larbi Krimbou, DES; Jacques Genest, MD

From the Department of Cardiovascular Genetics, McGill University Health Centre, Montréal, Canada.

Correspondence to Jacques Genest, MD, Director, Division of Cardiology, Royal Victoria Hospital, 687 Pine Ave, Montréal, QC H3A 1A1 Canada. E-mail jacques.genest{at}muhc.mcgill.ca

Background— Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C).

Methods and Results— We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI–mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia. A phospholipid efflux defect was defined as <70% of controls. Mean HDL-C was 0.49±0.21 mmol/L. Cholesterol and phospholipid efflux correlated strongly (r=0.72, P<0.001). Phospholipid efflux and HDL-C (r=0.64, P<0.001) correlated in HypoA subjects. However, phospholipid or cholesterol efflux was no longer a determinant of HDL-C levels at higher levels (>1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were identified (10 of 64; 16%). In the remaining 54 subjects, mean lipid efflux was not significantly different from controls and subjects with hyperalphalipoproteinemia. A phospholipid efflux defect was identified in 7 additional HypoA subjects, and a cholesterol efflux defect was detected in 11 subjects. In 2 of these subjects, the ABCA1 gene was ruled out as the cause of the efflux defect, while in 3, the low HDL-C trait segregated with the ABCA1 gene locus.

Conclusions— Lipidation of lipid-poor apolipoprotein AI may not be a major determinant of cholesterol accumulation within more mature HDL particles and increasing cholesterol or phospholipid efflux beyond normal levels may not lead to increase in plasma HDL-C levels. ABCA1 is essential in the initial steps of HDL formation but other plasma events are major modulators of HDL-C levels.

Key Words: lipoproteins • cholesterol • genetics • risk factors

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