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Identification of a novel human cellular HDL biosynthesis defect
European Heart Journal, 06/30/09

Rashid S et al. – Results indicate for the first time in humans that phospholipid and cholesterol efflux are 2 separate and distinct processes in cellular high-density lipoprotein (HDL) biosynthesis and that normal cellular phospholipid efflux is necessary for formation of larger {alpha}-HDL particles. Defective ABCA1 protein regulation results in a defect in phospholipid efflux, treatable with physiological oxysterols, a current therapeutic target that may serve to raise HDL levels in severe HDL deficiencies, pending further study.

• Study of the cellular basis of a novel HDL-deficiency phenotype
• Screen of 54 subjects of French Canadian ancestry with severe HDL deficiency
• Exclusion of pts with mutations in genes currently associated with low HDL (ABCA1, LCAT, APOA-I, and SMPD1)

• Cellular phospholipid efflux impaired in HDL biosynthesis process but cholesterol efflux normal in 2 pts
• On 2-dimensional gel electrophoresis analysis, the 2 impaired phospholipid efflux pts primarily defective in larger {alpha}-HDL subpopulations
• In fibroblasts from affected subjects, oxysterol stimulation resulted in increased ABCA1 protein expression and normalized defective phospholipid efflux defect

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