Dysfunctional high-density lipoprotein

Abstract

Purpose of review: To address the progress of the investigation on dysfunctional high-density lipoprotein (HDL).

Recent findings: HDL is generally considered to be an independent protective factor against cardiovascular disease. However, emerging evidence indicates that HDL can be modified under certain circumstances and lose its protective effect or even become atherogenic. The underlying mechanisms responsible for generating the dysfunctional HDL and the chemical and structural changes of HDL remain largely unknown. Recent studies focus on the role of myeloperoxidase in generating oxidants as participants in rendering HDL dysfunctional in vivo. Myeloperoxidase modifies HDL in humans by oxidation of specific amino acid residues in apolipoprotein A-I, which impairs cholesterol efflux through ATP-binding cassette transporter A1 and contributes to atherogenesis.

Summary: HDL may not always be atheroprotective and can be atherogenic paradoxically under certain conditions. The mechanisms responsible for generating the dysfunctional HDL remain largely unknown. Recent data suggest that myeloperoxidase-associated modification of HDL may be one of the mechanisms. Further studies are needed to investigate the in-vivo mechanisms of HDL modification and identify therapeutic approaches aiming at controlling HDL modification.

Figure 1. High-density lipoprotein metabolism and reverse cholesterol transport

Lipid-free apoA-I is produced in the intestine or liver or shed from the surface of triglyceride-rich lipoproteins during lipolysis. This particle initiates efflux of phospholipids and cholesterol from cell membranes that is facilitated by ABCA1. As the apoA-I adsorbs more lipids, it is converted into a hockey puck-like structure, nascent discoidal high-density lipoprotein (HDL). Cholesterol and phospholipid are esterified by the action of lecithin-cholesterol acyltransferase (LCAT) and then packed into the core of HDL. In macrophages, ABCA1 mediates cholesterol efflux to apoA-I. As more and more cholesteryl esters are incorporated into the particle, it becomes rounder and progressively larger (HDL₃–HDL₂). The reciprocal exchange of cholesteryl ester for triglycerides mediated by CETP moves the bulk of the cholesteryl esters to apoB-containing lipoproteins, which are eventually cleared by the liver through low-density lipoprotein (LDL) receptor (LDL-R). Peripheral cholesteryl esters can also be delivered to the liver through the binding of HDL to scavenger receptor B type I (SR-BI) and can also be secreted to bile.

Figure 2. High-density lipoprotein modification

High-density lipoprotein (HDL) modification can be classified into three types based on the nature of modification: spontaneous oxidative modification; enzyme-induced modification; and metabolic modification.

Figure 3. Myeloperoxidase-induced dysfunctional high-density lipoprotein

Myeloperoxidase (MPO) site specifically binds to apoA-I and produces reactive oxidative species that are responsible for the nitration and chlorination of tyrosine residues within apoA-I. Consequently, the modified high-density lipoprotein (HDL) impairs the ABCA1-dependent cholesterol efflux activity in macrophages.