Complex structure–function-disease relationships of HDL
Low plasma levels of High Density Lipoprotein (HDL) cholesterol (HDL-C) are associated with increased risks of coronary heart disease (CHD) (1). HDL particles exert many potentially anti-atherogenic functions and atherosclerosis could be decreased or even reverted in several animal models by increasing HDL-C through transgenic over-expression or xogenous application of apolipoprotein (apo) A-I) (3,4). Nevertheless the causal role of HDL in the pathogenesis of atherosclerosis has been increasingly questioned as the result of futile randomized controlled intervention trials with HDL-C increasing drugs as well as the lack of association between HDL-C altering genetic variants and risk of CHD in Mendelian randomization trials (1). However, the cholesterol in HDL (that is HDL-C) neither exerts nor reflects any of the potentially anti-atherogenic activities of HDL but is only a non-functional surrogate marker for estimating the HDL pool size without deciphering the heterogeneous composition and, hence, functionality of HDL (1,2). HDL particles carry hundreds of different quantitatively minor proteins and lipid species many of which are not just passive cargo (like cholesterol) but exert different functions beyond the stimulation of cholesterol efflux. Unfortunately, however, the relative importance of the many components and functions of HDL for the pathogenesis of atherosclerosis is unknown. In a systems biology approach, Cardner et al. (3) characterized the size distribution and the lipid and protein composition of HDL by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry as well as the functionality of HDL in five cellular systems. Using high-dimensional statistical modelling, specifically probabilistic graphical models of 40 clinical characteristics, 34 NMR features, 182 proteins, 227 lipid species, and 12 functional read-outs resulted in the following three main findings: First, CHD and diabetes are associated with different changes of HDL in protein and lipid composition as well as functionality. Second, different functions of HDL show rather little correlations with each other and are determined by different structural components. Of note cholesterol efflux capacity did not correlate with any other functionality and is hence not a proxy of HDL functionality in general. Third, and as a proof of principle, they validated the predicted functional relevance of one lipid species and two proteins, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes. Whether or not these molecules and candidate determinants of HDL function can serve as causal biomarkers and therapeutic targets must be investigated by follow-up studies.