HDL function and novel HDL-targeted therapies for preventing atherosclerotic cardiovascular disease: From mouse models to human disease

Abstract

Although significant evidence supports the concept that low high density lipoprotein cholesterol (HDL-C) is associated with an increased risk of cardiovascular disease (CVD), the failure of several HDL-targeted therapies to reduce CVD has cast doubts on the HDL-C hypothesis. Reverse cholesterol transport (RCT) is currently thought to be a major HDL cardioprotective property by which HDL promotes cholesterol efflux from macrophage foam cells and delivers that cholesterol to the liver, from where it will be partly eliminated through bile and feces. Beyond RCT, HDL exhibits other cardioprotective properties, such as antioxidant and anti-inflammatory effects. Data from genetically-engineered mice indicate that these HDL functions are closely associated with atherosclerosis susceptibility, thereby suggesting that the promotion of HDL functional properties may be considered a novel therapeutic strategy to reduce the atherosclerotic plaque burden and subsequent cardiovascular events. Furthermore, the potential anti-tumorigenic role of HDL is currently under investigation. This research has been essential for trying to translate experimental results obtained in mice to humans. The results of several recent human studies indicate that enhanced macrophage cholesterol efflux, the first step of RCT, is inversely associated with CVD events. Therefore, the current research is focused on improving HDL function rather than simply targeting HDL-C levels.

Keywords: HDL, cardiovascular disease, CETP, apoA-I, ATP-binding cassette, reverse cholesterol transport, nuclear receptors