Insights to HDL dysfunctionality: hypothesis of exhausted HDL

In recent years, a growing understanding of high-density lipoprotein (HDL) properties has significantly reshaped our comprehension of this crucial lipoprotein. Emerging evidence indicates that HDL can lose its well-documented protective functions, becoming dysfunctional and, paradoxically, even proatherogenic. Dysfunctional HDL (dys-HDL) is recognized as a critical contributor to cardiovascular disease and diabetes mellitus, conditions where cardiovascular complications are the main cause of mortality. The concept of dys-HDL appears broad, necessitating a distinction between HDL with diminished protective functionality and HDL that actively promotes proatherogenic effects. In certain conditions, the transition from protective to proatherogenic HDL appears to be a gradual and progressive process. This transition may be conceptualized through the idea of 'exhausted' HDL (ex-HDL), which represents HDL that has experienced reduced functionality but has not yet fully acquired proatherogenic characteristics. It signifies an abnormality leading to a state of 'partial functional impairment' in HDL. Hypothetically, dys-HDL could be categorized into two groups: ex-HDL and proatherogenic HDL. Such a classifying offers a path towards more targeted therapies for cardiovascular risk reduction. This review aims to enhance our understanding of HDL dysfunctionality and propose ex-HDL, thereby offering insights into the transition from protective to proatherogenic HDL.