High-Density Lipoprotein Proteomics: Identifying New Drug Targets and Biomarkers by Understanding Functionality
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High-Density Lipoprotein Proteomics: Identifying New Drug Targets and Biomarkers by Understanding Functionality Scott Gordon & Anita Durairaj & Jason L. Lu & W. Sean Davidson
Published online: 6 January 2010 # Springer Science+Business Media, LLC 2010
Abstract Recent proteomics studies on human plasma high-density lipoprotein (HDL) have discovered up to 50 individual protein constituents. Many of these have known functions that vary surprisingly from the lipid transport roles commonly thought to mediate HDL’s ability to protect from coronary artery disease. Given newly discovered roles in inflammation, protease inhibition, complement regulation, and innate immunity, many have begun to view HDL as a broad collection of distinct particle subfamilies, each distinguished by unique protein compositions and functions. Herein we review recent applications of highresolution proteomics to HDL and summarize evidence supporting the idea of HDL functional subspeciation. These studies have set the stage for a more complete understanding of the molecular basis of HDL functional heterogeneity and hold promise for the identification of new biomarkers that can predict disease or evaluate the success of clinical interventions.
S. Gordon : A. Durairaj : W. S. Davidson (*) Center for Lipid and Arteriosclerosis Science, University of Cincinnati, 2120 East Galbraith Road, Cincinnati, OH 45237-0507, USA e-mail: [email protected] S. Gordon e-mail: [email protected] A. Durairaj e-mail: [email protected] J. L. Lu Division of Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, 3333 Burnet Avenue, MLC 7024, Cincinnati, OH 45229-3039, USA e-mail: [email protected]
Keywords High density lipoprotein . Proteomics . Mass spectrometry . Lipoprotein . Apolipoprotein . Reverse cholesterol transport . Cardiovascular disease . Protein
Introduction Epidemiologic studies dating back to the 1960s have shown that increased plasma high-density lipoprotein (HDL) cholesterol levels are a powerful negative risk factor for development of coronary artery disease (CAD) in a given population. HDL is a blood-borne assembly of amphipathic proteins (∼50% by mass) that stabilize lipid emulsions composed of phospholipids (∼25%), cholesterol (∼4%), triglycerides (∼3%), and cholesteryl esters (∼12%). In addition to structural stability, these proteins (termed apolipoproteins) impart biological directionality to the lipid cargo by 1) targeting it to various tissues, 2) modifying its chemical form (ie, lipolysis or esterification), or 3) transferring it to other lipoproteins. Roughly 65% of HDL protein mass is comprised of apolipoprotein (apo)A-I with another 15% by apoA-II. The remainder includes around 50 proteins that are each too low in abundance to be present on all circulating HDL particles. The potential for differential accumulation of these proteins into certain subspecies likely drives the well-known polydispersity of HDL. Such compositional variability suggests that HDL mediates numerous and highly diverse biological roles, a
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