Abstract
While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.
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The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: these studies were supported by National Institute for Health and Medical Research (INSERM; Paris, France) and Sorbonne University (Paris, France). We gratefully acknowledge further support from ICAN (Paris, France) and China Scholarship Council (CSC, China).
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IG, AK, and WLG designed the experiments; IG, MD, FM and MD performed the experiments; IG and SL performed the LPLC experiments; ML performed the lipidomic and CP and LM the proteomic analysis; PC, PG, PEK and MA performed the clinical assessments, and Tangier patient recruitment; MP performed the statistical and bioinformatics analysis; IG, AK, and WLG analysed the data; IG, PL, MG, AK, and WLG wrote the manuscript. All the authors gave critical comments on the manuscript.
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The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AK reports grants from CSL and Pfizer, personal fees from American Heart Association, National Lipid Association, Sanofi and European Society of Cardiology, outside the submitted work.
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Guillas, I., Lhomme, M., Pionneau, C. et al. Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease. Basic Res Cardiol 118, 33 (2023). https://doi.org/10.1007/s00395-023-01004-2
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DOI: https://doi.org/10.1007/s00395-023-01004-2