High-Density Lipoprotein Function and Dysfunction in Health and Disease

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.

Keywords: Atherosclerosis; Cardiovascular disease; HDL dysfunction; Inflammation.

Fig. 1

Potential mechanisms linking dysfunctional HDL to vascular damage. In the absence of inflammation (top), HDL exerts vascular protective effects through its ability to increase endothelial NO bioavailability, decrease oxidative stress, and inhibit the expression of adhesion molecules on the vascular wall. In inflammatory states (bottom), however, numerous structural and functional changes may occur and compromise endothelial function. Beneficial proteins contained within the particle (e.g. ApoA-I, PON-1) are liable for oxidation or replacement, resulting in a noxious particle which impairs NO generation, amplifies oxidative stress, and promotes adhesion molecule expression and monocyte infiltration across the vascular wall

Fig. 2

Mechanistic pathways underlying reverse cholesterol transport from macrophages to liver. HDL-mediated RCT involves the removal of cholesterol from lipid-laden macrophages, where it may then be transported back to the liver for biliary excretion. In healthy individuals, nascent and mature HDL particles accept cholesterol from lipid-laden macrophages within the vascular wall via an interaction of ApoA-I with ABCA1 and ABCG1 receptors. Following their esterification by the enzyme LCAT, these cholesterol particles may undergo selective uptake to the liver via the interaction of HDL and hepatic SR-BI, or may be transferred by CETP to VLDL/LDL for hepatic uptake via LDL-R. In conditions of chronic disease or inflammation, numerous changes in this pathway have been observed that may render it dysfunctional and potentially increase atherosclerotic risk. These changes include the oxidation or displacement of ApoA-I, alterations in the activity of enzymes such as LCAT or CETP, and reduced binding of HDL to receptors such as ABCG1 or SR-BI