Advances in Understanding HDL Functionality: Paradigms Beyond the Reverse Cholesterol Transport

The field of cardiovascular research has long examined the relationship between high-density lipoproteins (HDL) and coronary artery disease (CAD). Numerous clinical and epidemiological studies have demonstrated a strong inverse correlation between HDL cholesterol (HDL-C) plasma levels and CAD risk. This evidence has strongly supported an anti-atherogenic role for HDLs, mainly due to their involvement in reverse cholesterol transport (RCT). However, the evidence from evolutionary biology showing the conservation of the Apo AI gene from cartilaginous fishes to mammals suggests that HDLs fulfill vital functions that, under certain circumstances, overlap with the protection of coronary arteries against atherosclerosis. In this context, a reevaluation of HDL function is needed, with different perspectives than the RCT.

Despite efforts to leverage RCT in therapeutic developments, several drugs have been designed to increase HDL-C levels, but they have failed to decrease CAD risk. In addition, individuals with APOAI mutations, such as apo-AI Milano or apo-AI Paris, who maintain low HDL-C levels without increased CAD occurrence, challenge the traditional view of HDL as solely protective for coronary health. Moreover, alterations in HDL profiles have been observed in acute states such as coronary syndrome, trauma, inflammation, and physiological states such as pregnancy and senescence. Still, their impact and causal relationship remain unclear. This growing body of evidence questions the exclusivity of RCT in the atheroprotective role of HDLs and encourages the exploration of new paradigms to understand the physiological significance of HDL. This Research Topic aims to integrate the existing knowledge on the diverse functions of HDLs under various health conditions and promote the generation of new paradigms in understanding the physiological role of these lipoproteins.

We welcome the submission of basic and translational research. We are particularly interested in original research and review articles that redefine the scope of HDL functionality and challenge traditional perspectives that limit HDLs to RCT roles. We hope to illuminate the multifaceted roles of HDLs in health and disease beyond CAD. We welcome articles addressing, but not limited to, the following themes:

- The role of HDLs in conditions such as trauma and tissue repair

- The impact of HDL throughout life: from fetal and neonatal development to cellular senescence

- The role of HDL in the development and progression of insulin resistance, diabetes, obesity and cancer

- The role of HDL in neuronal maintenance and function

- Novel therapeutic interventions targeting HDL functionality beyond RCT