Skip Navigation


European Heart Journal Advance Access originally published online on June 24, 2009
European Heart Journal 2009 30(18):2204-2212; doi:10.1093/eurheartj/ehp250
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
30/18/2204    most recent
ehp250v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Rashid, S.
Right arrow Articles by Genest, J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rashid, S.
Right arrow Articles by Genest, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Identification of a novel human cellular HDL biosynthesis defect

Shirya Rashid1,*, Michel Marcil2, Isabelle Ruel2 and Jacques Genest2

1 Department of Medicine, Henderson Research Centre, McMaster University, G-Wing, Rm 206, 711 Concession Street, Hamilton, ON, Canada L8V 1C3
2 Cardiovascular Research Laboratories, McGill University Health Centre, McGill University, Montreal, Québec, Canada

Received 25 February 2009; accepted 4 June 2009; online publish-ahead-of-print 24 June 2009.

* Corresponding author. Tel: +1 905 527 2299 ext. 43780, Fax: +1 905 575 2646, Email: srashid{at}thrombosis.hhscr.org

Aims: 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.

Methods and 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.

Conclusion: 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.

Key Words: HDL • Cholesterol • Phospholipid • Dyslipidaemia • Apolipoprotein A-I • ABCA1 • Efflux • LXR


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.