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.
Highlights
high-density lipoprotein cholesterol (HDL-C) was considered the “good cholesterol”, and it was hypothesized that the epidemiological association of high HDL-C with less coronary heart disease (CHD) was because HDL was causally protective against atherosclerosis in humans
The function of HDL in this part of the reverse cholesterol transport (RCT) pathway can be estimated via the cholesterol efflux capacity (CEC) assay, in which apolipoprotein B (apoB)-depleted human serum from different donors is used as the cholesterol acceptor (Figure 1)
In a large prospective cohort, we found that the subjects in the lowest quartile of apoA1 exchange rate (AER) had increased incident major adverse cardiovascular events (MACEs) after adjustment for traditional risk factors including HDL-C and apoA1 levels [89]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. HDL has been attributed with many different protective effects and pathways in addition to the abovementioned RCT, including cholesterol delivery to steroidogenic organs, anti-inflammatory effects on endothelial cells and macrophages, anti-apoptotic effects on endothelial cells, antithrombotic effects, re-endotheliazation of injured arteries, and anti-oxidant activity [6,7]. The RCT effect on reducing atherosclerosis in mice was proven via bone marrow transplantation studies using wild-type or ABCA1-deficient donors. Macrophages, such as those in atherosclerotic lesions, from the ABCA1-deficient donors could not generate nascent HDL from apoA1, and these mice had larger lesions [10]. HDL-C was considered the “good cholesterol”, and it was hypothesized that the epidemiological association of high HDL-C with less CHD was because HDL was causally protective against atherosclerosis in humans
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