HDL proteome: from its characterization to quantitative measurements in particle subspecies and functional associations

Recent failures of therapeutic interventions aimed at elevating high-density lipoprotein cholesterol (HDL-C) have renewed the need to reconceptualize HDL. The HDL proteome constitutes over 50% of the HDL mass and it is the richest among lipoproteins. HDL is also the most heterogeneous lipoprotein, and unraveling the determinants of its pleiotropic functions requires new approaches to characterize HDL subspecies as well as harmonization of isolation and quantification methodologies. We have reviewed studies focusing on HDL proteomes from the past 5 years, with particular focus on recent developments in mass spectrometry-based proteomics applied to HDL, and the studies of HDL heterogeneity and function. Emphasis is also given on the quantification of the proteome of HDL-specific subspecies and on the studies relating the HDL proteome to its function. We further discuss the need for harmonization in HDL subpopulations and subspecies isolation and in proteome quantification. The HDL proteome is undisputedly related to the HDL function. The development of new approaches to isolate HDL subspecies, together with the implementation of consistent quantification strategies, is needed to provide new insights into the structure–function relationship of HDL particles, unravel the role of HDL in the pathology of diseases, and provide new metrics of HDL.