HDLs in crises

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Purpose of review

The clinical utility of HDLs has been scrutinized upon the publication of Mendelian randomization studies showing no effect of HDL-cholesterol (HDL-C) modifying variants on cardiovascular disease (CVD) outcome. The failures of randomized controlled HDL-C-directed intervention trials have further fueled this skepticism. This general criticism originates from oversimplification that has equated ‘HDL-C’ with ‘HDL’ and misconceived both as the ‘good cholesterol’.

Recent findings

HDL particles are heterogeneous and carry hundreds of different lipids, proteins, and microRNAs. Many of them but not cholesterol, that is, HDL-C, contributes to the multiple protective functions of HDLs that probably evolved to manage potentially life-threatening crises. Inflammatory processes modify the composition of HDL particles as well as their individual protein and lipid components, and, as a consequence, also their functionality. Gain of dominant-negative functions makes dysfunctional HDL a part rather than a solution of the endangering situation. Quantification of HDL particle numbers, distinct proteins or lipids, and modifications thereof as well as bioassays of HDL functionality are currently explored toward their diagnostic performance in risk prediction and monitoring of treatment response.


Any successful clinical exploitation of HDLs will depend on the identification of the most relevant (dys)functions and their structural correlates. Stringent or prioritized structure-(dys)function relationships may provide biomarkers for better risk assessment and monitoring of treatment response. The most relevant agonists carried by either functional or dysfunctional HDLs as well as their cellular responders are interesting targets for drug development.

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