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Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular
Isabelle Guillas1, Marie Lhomme2, Cédric Pionneau3
1Inserm, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, Hôpital de la Pitié, Sorbonne Université, 75013, Paris, France. isabelle.guillas_baudouin@sorbonne-universite.fr.
Insights
Small, dense pre-beta high-density lipoprotein (HDL) particles, crucial for cardiovascular health, were successfully isolated. These particles show unique lipid and protein profiles, potent cholesterol efflux, and anti-inflammatory effects, offering new diagnostic targets.
Area of Science:
- Cardiovascular Biology
- Lipid Metabolism
- Immunology
Background:
- Low high-density lipoprotein-cholesterol (HDL-C) is a cardiovascular risk factor, yet HDL-C-raising therapies have largely failed.
- HDL particles are heterogeneous; small, dense pre-beta-HDLs are biologically active but difficult to study.
- Understanding pre-beta-HDL composition and function is key to novel cardiovascular disease (CVD) therapies.
Purpose of the Study:
- To develop a method for isolating sufficient quantities of human pre-beta-HDLs.
- To characterize the specific proteomic and lipidomic profiles of pre-beta-HDLs.
- To investigate the biological activities and potential therapeutic relevance of pre-beta-HDLs.
Main Methods:
- Developed an original experimental approach for pre-beta-HDL isolation.
- Performed proteomic and lipidomic analyses to identify constituent molecules.
- Assessed biological activities, including cellular cholesterol efflux and anti-inflammatory effects.
- Utilized correlational network analysis to link molecular components with biological functions.
Main Results:
- Successfully isolated substantial amounts of human pre-beta-HDLs.
- Identified unique lipid profiles, enriched in specific phosphatidic acid and phosphatidylserine species.
- Revealed enrichment of inflammatory response proteins (e.g., paraoxonase-1, vitronectin, clusterin) and immune-related proteins (e.g., haptoglobin-related protein, complement proteins, immunoglobulins).
- Found enrichment of key lipid metabolism proteins (PLTP, CETP, LCAT) within pre-beta-HDLs.
- Demonstrated potent cholesterol efflux and significant anti-inflammatory activities of pre-beta-HDL.
- Highlighted 15 lipid and protein components as potential diagnostic targets for CVD.
Conclusions:
- Pre-beta-HDL particles possess distinct lipid and protein compositions with significant biological functions.
- These findings provide novel insights into HDL heterogeneity and its role in cardiovascular health.
- Identified pre-beta-HDL components may serve as future diagnostic biomarkers or therapeutic targets for cardiovascular disease.
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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