HDL Is Not Dead Yet

Abstract

High-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with coronary heart disease (CHD) in multiple epidemiological studies, but whether HDL is causal or merely associated with CHD is unclear. Recent trials for HDL-raising drugs were either not effective in reducing CHD events or, if beneficial in reducing CHD events, were not conclusive as the findings could be attributed to the drugs' LDL-reducing activity. Furthermore, the first large Mendelian randomization study did not causally relate HDL-C levels to decreased CHD. Thus, the hypothesis that HDL is protective against CHD has been rightfully challenged. However, subsequent Mendelian randomization studies found HDL characteristics that are causally related to decreased CHD. Many aspects of HDL structure and function, especially in reverse cholesterol transport, may be better indicators of HDL's protective activity than simply measuring HDL-C. Cholesterol efflux capacity is associated with lower levels of prevalent and incident CHD, even after adjustment for HDL-C and apolipoprotein A-1 levels. Also, subjects with very high levels of HDL-C, including those with rare mutations that disrupt hepatic HDL uptake and reverse cholesterol transport, may be at higher risk for CHD than those with moderate levels. We describe here several cell-based and cell-free in vitro assays of HDL structure and function that may be used in clinical studies to determine which of HDL's functions are best associated with protection against CHD. We conclude that the HDL hypothesis may need revision based on studies of HDL structure and function, but that the HDL hypothesis is not dead yet.

Keywords: HDL function; Mendelian randomization; apoA1 exchange rate; coronary heart disease; inflammation; reverse cholesterol transport.

Figure 1

Assays for HDL function that represent the role of HDL in reverse cholesterol transport and HDL remodeling. The cholesterol efflux capacity assay uses human apoB-depleted serum as an acceptor for macrophage cholesterol and phospholipids. ABCA1 mediates cellular cholesterol and phospholipid efflux onto serum lipid-poor apoA1 leading to the formation of nHDL, which represents the ABCA1-dependent cholesterol efflux capacity. Serum HDL can accept more cholesterol and phospholipid through ABCG1, SR-BI, and aqueous diffusion, which represents the ABCA1-independent cholesterol efflux capacity. This assay can distinguish between ABCA1-dependent and -independent cholesterol efflux when using mouse macrophages as the donor cell type. The apoA1 exchange-rate assay is a cell-free in vitro assay in which human apoB-depleted serum or plasma is incubated with exogenously labeled apoA1, and apoA1 is freely exchangeable between labeled lipid-free apoA1 and serum HDL. The rate of exchange of the labeled apoA1 is an indicator of HDL remodeling and is correlated with plasma HDL and apoA1, as well as with the cholesterol efflux capacity. ABCA1: ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; SR-BI: scavenger receptor B I; ApoA1: apolipoprotein A-I; nHDL: nascent high-density lipoprotein; LCAT: lecithin:cholesterol acyltransferase; CETP: cholesteryl ester transfer protein; PLTP: phospholipid transfer protein; VLDL: very low-density lipoprotein; IDL: intermediate-density lipoprotein; LDLR: low-density lipoprotein receptor.