High-density lipoprotein heterogeneity and function in reverse cholesterol transport

Abstract

Purpose of review: HDL is a cardioprotective lipoprotein, at least in part, because of its ability to mediate reverse cholesterol transport (RCT). It is becoming increasingly clear that the antiatherogenic effects of HDL are not only dependent on its concentration in circulating blood but also on its biological 'quality'. This review summarizes our current understanding of how the biological activities of individual subclasses of HDL particles contribute to overall HDL performance in RCT.

Recent findings: Recent work indicates that apolipoprotein A-I-containing nascent HDL particles are heterogeneous and that such particles exert different effects on the RCT pathway. RCT from macrophages has been examined in detail in mice and the roles of plasma factors (lecithin-cholesterol acyltransferase, cholesterol ester transfer protein, phospholipid transfer protein) and cell factors (ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, scavenger receptor class B type 1) have been evaluated. Manipulation of such factors has consistent effects on RCT and atherosclerosis, but the level of plasma HDL does not reliably predict the degree of RCT. Furthermore, HDL cholesterol or apolipoprotein A-I levels do not necessarily correlate with the magnitude of cholesterol efflux from macrophages; more understanding of the contributions of specific HDL subspecies is required.

Summary: The antiatherogenic quality of HDL is defined by the functionality of HDL subspecies. In the case of RCT, the rate of cholesterol movement through the pathway is critical and the contributions of particular types of HDL particles to this process are becoming better defined.

Figure 1. Factors contributing to the structural heterogeneity of HDL particles

Different subclasses of the depicted spherical HDL particle can be isolated on the basis of differences in particle diameter and density (lipid/protein ratio). Variations in the surface charge lead to subclasses that can be separated due to differences in electrophoretic mobility. Differences in apolipoprotein composition permit isolation of HDL particles containing either apoA-I alone (LpA-I) or apoA-I along with apoA-II (LpA-I + A-II) by immunoaffinity methods. HDL particles can also be distinguished by their shape: spherical plasma HDL particles contain a neutral lipid core, whereas the discoidal HDL particles that occur in lymph do not. See text for further details. CE, cholesterol ester; TG, triacylglycerol.

Figure 2. Schematic overview of the major pathways involved in HDL-mediated macrophage cholesterol efflux and reverse cholesterol transport to the liver

ApoA-I is produced by the liver and acquires free cholesterol and phospholipid from liver and peripheral cells (including macrophages) via the ATP-binding cassette transporter A1 (ABCA1) to form nascent (discoidal) HDL particles. Nonlipidated apoA-I is cleared by the kidney. Free cholesterol efflux from macrophages to HDL particles is also promoted by the ABCG1 transporter and scavenger receptor class B type 1 (SR-BI). As discussed in section ‘HDL heterogeneity’, the free cholesterol in discoidal HDL particles is converted to cholesteryl ester by lecithin-cholesterol acyltransferase (LCAT) activity leading to the formation of mature, spherical HDL particles. Phospholipid transfer protein (PLTP) mediates transfer of phospholipids from VLDL into HDL, thereby providing phospholipids for the LCAT reaction. Mature HDL particles can be remodeled to smaller particles with the release of apoA-I by the actions of hepatic lipase and endothelial lipase, which hydrolyze HDL triglycerides and phospholipids, respectively (Table 2). In humans, but not rodents, HDL cholesterol ester can be transferred to the VLDL/LDL pool by cholesteryl ester transfer protein (CETP) and taken up by endocytosis into hepatocytes via interaction with the LDL receptor (LDLR). HDL cholesterol ester and free cholesterol are also transferred directly to hepatocytes via SR-BI-mediated selective uptake. Cholesterol taken up by the liver can be recycled back into the ABCA1 pathway, secreted into bile as either free cholesterol or bile acids, or assembled into lipoprotein particles that are secreted back into the circulation (not shown). CE, cholesterol ester; FC, free cholesterol; TG, triacylglycerol.