Abstract
High-density lipoprotein cholesterol (HDL-c) has long been referred to as ‘good cholesterol’ due to its apparent inverse relationship with future CVD risk. More recent research has questioned a causal role for HDL-c in this relationship, however, as both genetic studies and numerous large-scale randomised controlled trials have found no evidence of a cardiovascular protective effect when HDL-c levels are raised. Instead, focus has switched to the functional properties of the HDL particle. Evidence suggests that both the composition and function of HDL may be significantly altered in the context of an inflammatory milieu, transforming the particle from a vasoprotective anti-atherogenic particle to a noxious pro-atherogenic equivalent. This review will summarise evidence relating HDL to CVD risk, explore recent evidence characterising changes in the composition and function of HDL that may occur in chronic inflammatory diseases, and discuss the potential for future HDL-modifying therapeutic interventions.
Highlights
High-density lipoproteins (HDL) participate in the transfer of excess cholesterol from peripheral sites to the liver, and the cholesterol carried within these lipoproteins (HDL-c) is often referred to as ‘good cholesterol’
Of particular importance in chronic kidney disease (CKD) is a significant increase in the acute phase protein symmetric dimethylarginine (SDMA), whose incorporation into the HDL particle is associated with impairments in HDL-mediated reverse cholesterol transport (RCT) and endothelial nitric oxide (NO) production in a dose-dependent manner [43, 70, 77]
These results suggest that interventions to modify HDL function, rather than increasing High-density lipoprotein cholesterol (HDL-c) levels—may still hold therapeutic potential for reducing atherosclerotic risk
Summary
High-density lipoproteins (HDL) participate in the transfer of excess cholesterol from peripheral sites to the liver, and the cholesterol carried within these lipoproteins (HDL-c) is often referred to as ‘good cholesterol’. Findings from two separate Mendelian Randomization studies containing over 165,000 participants found no association between genetically determined HDL-c and risk of myocardial infarction, despite traditional observational relationships from the same cohorts displaying the expected inverse relationship with plasma levels of HDL-c [1, 2] These findings challenged the concept that elevating HDLc would translate into clinical benefit, and these concerns were later confirmed by negative findings from numerous randomised clinical trials investigating a number of different HDL-raising drugs. More recent evidence has highlighted the presence of numerous structural and functional changes in the HDL particle that may result in its transformation from an anti-atherogenic vasoprotective particle to a pro-inflammatory noxious equivalent (Fig. 1) These alterations are most commonly observed in the presence of systemic inflammation, and suggest an evolutionary role for HDL in the innate immune response, where the greatest threat to human longevity has long come from viral or bacterial infections [15]. HDL Structure and Function in Healthy Individuals: an Anti-atherogenic Particle Exerting Multiple Vasoprotective Effects
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have