HDL, Atherosclerosis, and Emerging Therapies

Abstract

This review aims to provide an overview on the properties of high-density lipoproteins (HDLs) and their cardioprotective effects. Emergent HDL therapies will be presented in the context of the current understanding of HDL function, metabolism, and protective antiatherosclerotic properties. The epidemiological association between levels of HDL-C or its major apolipoprotein (apoA-I) is strong, graded, and coherent across populations. HDL particles mediate cellular cholesterol efflux, have antioxidant properties, and modulate vascular inflammation and vasomotor function and thrombosis. A link of causality has been cast into doubt with Mendelian randomization data suggesting that genes causing HDL-C deficiency are not associated with increased cardiovascular risk, nor are genes associated with increased HDL-C, with a protective effect. Despite encouraging data from small studies, drugs that increase HDL-C levels have not shown an effect on major cardiovascular end-points in large-scale clinical trials. It is likely that the cholesterol mass within HDL particles is a poor biomarker of therapeutic efficacy. In the present review, we will focus on novel therapeutic avenues and potential biomarkers of HDL function. A better understanding of HDL antiatherogenic functions including reverse cholesterol transport, vascular protective and antioxidation effects will allow novel insight on novel, emergent therapies for cardiovascular prevention.

Figure 1

Schematic diagram of HDL metabolic pathways and current drugs under development. Numbers in circles refer to Table 2. Pathway influencing HDL cholesterol metabolism, flux, and potential targets of therapeutic interventions. Both liver and intestine synthesize apolipoprotein A-I (ApoA-I) secreted as lipid-poor particles. These particles are lipidated with phospholipids and cholesterol via the hepatocyte ATP-binding cassette A1 (ABCA1) transporter to form nascent HDL. In peripheral tissues these HDL particles obtain free cholesterol via the macrophage ABCA1 and ABCG1 transporters, which are regulated by LXRs and miR-33. Free cholesterol transferred via ABCA1 and ABCG1 onto HDL is esterified by lecithin: cholesterol acyltransferase (LCAT) to form cholesteryl esters (CE). Mature HDL thus formed exchange CE trough cholesteryl ester transfer protein (CETP) onto apoB-containing lipoproteins, (VLDL and LDL) with subsequent uptake in the liver via the low-density lipoprotein receptor (LDLR). PLTP mediates transfer of phospholipid from triglyceride from VLDL into HDL, which promote HDL remodeling. The resulting HDL3 particles can be either taken up by the liver via SB-B1 or modified by hepatic lipase (HL) and endothelial lipase (EL), which hydrolyze HDL phospholipids and triglycerides. Metabolism by EL releases lipid-poor apoA-I, which can be catabolized in kidney. Targets of HDL-directed therapeutic interventions are indicated by red arrow.

Figure 2

HDL biogenesis. Mitochondrial cholesterol transport is rate limiting in the (sterol 27-hydroxylase-) dependent generation of oxysterol ligands for LXR (liver X receptor) transcription factors that regulate the expression of genes encoding proteins in the cholesterol efflux pathway, such as ABC transporters (ATP-binding cassette transporters) ABCA1, and ABCG1. These transporters transfer cholesterol and/or phospholipids across the plasma membrane to (apo) lipoprotein acceptors, generating nascent HDLs (high-density lipoproteins), which can safely transport excess cholesterol through the bloodstream to the liver for excretion in bile. Ligand activation of nuclear LXRs (liver X receptors) (LXRα/β) is pivotal in cellular response to elevated sterol content, triggering cholesterol efflux mechanisms: both synthetic and oxysterol LXR agonists potently upregulate ABCA1 and ABCG1 gene expression. Consequently, elimination of excess cholesterol can be achieved, in vivo and in vitro, by cellular cholesterol efflux, orchestrated by ABCA1, ABCG1, ABCG4, and passive diffusion along a concentration gradient, and also “acceptor” (apo) lipoproteins, such as apoA-I, and HDLs (high-density lipoproteins). Notably, LXRs form heterodimers with RXRs (retinoic acid receptors) and bound to the nuclear receptor.

Figure 3

Summary of pleiotropic effects of HDL. In addition to their ability to reverse transport cholesterol from peripheral tissues back to the liver, HDLs display pleiotropic effects including antioxidant, antiapoptotic, anti-inflammatory, anti-infectious, and antithrombotic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide (NO) is also a hallmark of HDL action on those cells.