title: Identification of a novel human cellular HDL biosynthesis defect.
abstract: OBJECTIVE
  Severe high-density lipoprotein cholesterol (HDL-C) deficiency is attributed to mutations in several genes and may contribute to the genetic basis of coronary artery disease. To identify the cellular basis of a novel HDL-deficiency phenotype, we screened 54 subjects of French Canadian ancestry with severe HDL deficiency.
  
  
  RESULTS
  We excluded individuals with mutations in genes currently associated with low HDL (ABCA1, LCAT, APOA-I, and SMPD1). We identified two patients in which cellular phospholipid efflux in the HDL biosynthesis process is impaired, whereas cholesterol efflux is normal. Two-dimensional gel electrophoresis analysis further showed that the two patients with impaired phospholipid efflux were defective primarily in the larger alpha-HDL subpopulations. In fibroblasts from affected subjects, oxysterol stimulation resulted in increased ABCA1 protein expression and normalized their defective phospholipid efflux defect.
  
  
  CONCLUSIONS
  Our results indicate for the first time in humans that phospholipid and cholesterol efflux are two separate and distinct processes in cellular HDL biosynthesis. They further show for the first time that normal cellular phospholipid efflux is necessary for the formation of larger alpha-HDL particles. The defect in phospholipid efflux is due to defective ABCA1 protein regulation and can be corrected by treatment with physiological oxysterols, a current therapeutic target of interest, that may, with further studies, be used to raise HDL levels in patients with severe HDL deficiencies.
authors: Department of Medicine, Henderson Research Centre, McMaster University, G-Wing, Rm 206, 711 Concession Street, Hamilton, ON, Canada. srashid@thrombosis.hhscr.org
authors: Shirya
authors: S
authors: Rashid
authors: Michel
authors: M
authors: Marcil
authors: Isabelle
authors: I
authors: Ruel
authors: Jacques
authors: J
authors: Genest
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D001053:Apolipoproteins / Q000378:metabolism; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000096:biosynthesis / Q000172:deficiency*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D013631:Tangier Disease / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001053:Apolipoproteins; D008076:Cholesterol, HDL; D012333:RNA, Messenger