The Birth of the HDL Hypothesis

Add this Moment to your Passport

Learn from this moment and keep it forever.
Add To Passport



The Birth of the HDL Hypothesis

It is a well-established fact that elevated plasma concentrations of low-density lipoprotein-cholesterol (LDL-C) is one of the most important risk factors for developing coronary artery disease (CAD), and, eventually, coronary heart disease (CHD)1 and other forms of atherosclerotic cardiovascular disease (CVD). Targeting LDL-C reduction has been effective in lowering CVD risk, through the use of HMG-CoA reductase inhibitors (statins) for both primary and secondary CVD prevention as the first-line therapy, resulting in reduced CV events and overall mortality2,3. However, despite reduction in LDL-C, 18–41 % with moderate doses of statins and 40–60 % with higher doses or more potent statins, there remains a significant residual cardiovascular risk. In the late 1970s the inverse relationship between plasma concentration of HDL-C and CVD risk was identified4 and subsequent prospective data from the Framingham Heart and ARIC studies further supported this idea5,6. It was proposed that CHD risk was inversely related to plasma concentration of HDL-C, owing to the ability of HDL particles to remove cholesterol from developing atherosclerotic lesions, and thus, the HDL hypothesis was conceived. Subsequent in vivo studies, in which plasma HDL-C was raised by infusion or transgenic expression of human apolipoprotein AI (ApoAI) in rabbit and mouse models of atherosclerosis demonstrated a potent atheroprotective effect7–9. With this wide array of potential benefits, raising plasma HDL-C was seen as a promising new drug target.

Raising Plasma Concentration of HDL-C

Although lifestyle changes, such as vigorous exercise, smoking cessation and weight loss have been shown to moderately increase plasma concentrations of HDLs10–13, individuals with low plasma HDL-C are more likely to respond to pharmacological treatment that increases HDL. Whilst statins, fibrates and some thiazolidenediones have been shown to modestly increase plasma concentrations of HDL-C14–16, nicotinic acid or niacins have been used to provide a more robust increase by 15–16 %17,18. Niacin increases plasma HDL-C by inhibiting the putative hepatocyte HDL-C catabolism receptor, preventing HDL-C catabolism, and thereby increasing the half-life of circulating HDL-C18. However, neither of the two large randomised controlled clinical trials, AIM-HIGH and HPS2-THRIVE, were able to demonstrate a difference in the primary end point despite favourable changes in HDL-C concentration17,18. Although these data may question the ability to provide a cardioprotective effect through elevating plasma HDL-C, nicotinic acid and niacins have dramatic side effects, such as flushing, which may well compromise any benefits observed.

CETP as a Novel Drug Target to Raise Plasma Concentration of HDLs.Image title

Development of a novel target for elevating plasma HDL-C concentration was derived from analysis of the understanding of the biochemistry of HDL metabolism and particle dynamics. CETP is a hydrophobic glycoprotein which can catalyse the transfer of cholesteryl esters, generated by lecithin:cholesterol acyltransferase (LCAT), principally in larger -HDLs, to other lipoproteins in exchange for triglycerides (TGs), derived primarily from very low-density lipoproteins (VLDL) or chylomicrons19 (Figure 1). This process of lipid exchange has been shown to increase the relative abundance of small lipid-poor pre -HDL particles, which play a primary role in the acquisition of cholesterol from cell membranes via the ABCA1 transporter (reverse cholesterol transport)20. These data seeded the idea that modulation of HDL particle abundance could increase the ability to remove cholesterol from peripheral tissues, and was further supported by numerous in vivo studies where inhibition of CETP in animal models prevented cholesterol-induced atherosclerosis21–23, whilst CETP gene transfer in mice (a species lacking CETP activity) increased lesion formation21. Although these findings were encouraging, subsequent studies in other models did not reiterate the protective effect of CETP inhibition shown previously24–26. However, these data are difficult to compare and may reflect disparity in means by which CETP is modulated and in the mechanisms involved in generating atheromatous lesions in the specific models. In an extremely elegant set of experiments, Brousseau and colleagues were able to show, that raising HDL-C using the CETP-inhibitor drug, torcetrapib, did so through an effect on delaying catabolism27. Both torcetrapib and niacin increase HDL by delaying catabolism, which, in turn, increases the half-life of HDL-C, but neither of these methods have led to a beneficial clinical effect. As HDLs are heterogeneous, dynamic particles, it is likely that their structure and function will be significantly modified by prolonging the circulatory half-life and would depend largely on the effect of the clinical status of the patient.

Loading Simple Education