Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit

Abstract

Uptake of low-density lipoprotein (LDL) particles by macrophages represents a key step in the development of atherosclerotic plaques, leading to the foam cell formation. Chemical modification of LDL is however necessary to induce this process. Proatherogenic LDL modifications include aggregation, enzymatic digestion and oxidation. LDL oxidation by one-electron (free radicals) and two-electron oxidants dramatically increases LDL affinity to macrophage scavenger receptors, leading to rapid LDL uptake and fatty streak formation.Circulating high-density lipoprotein (HDL) particles, primarily small, dense, protein-rich HDL3, provide potent protection of LDL from oxidative damage by free radicals, resulting in the inhibition of the generation of pro-inflammatory oxidized lipids. HDL-mediated inactivation of lipid hydroperoxides involves their initial transfer from LDL to HDL and subsequent reduction to inactive hydroxides by redox-active Met residues of apolipoprotein A-I. Several HDL-associated enzymes are present at elevated concentrations in HDL3 relative to large, light HDL2 and can be involved in the inactivation of short-chain oxidized phospholipids. Therefore, HDL represents a multimolecular complex capable of acquiring and inactivating proatherogenic lipids.Antioxidative function of HDL can be impaired in several metabolic and inflammatory diseases. Structural and compositional anomalies in the HDL proteome and lipidome underlie such functional deficiency. Concomitant normalization of the metabolism, circulating levels, composition and biological activities of HDL particles, primarily those of small, dense HDL3, can constitute future therapeutic target.

The Role and Function of HDL in Patients with Chronic Kidney Disease and the Risk of Cardiovascular Disease

“…Study results have indicated that higher activity of PON1 was associated with a lower incidence of major cardiovascular events in humans. HDL-associated LCAT exerts its antioxidative properties via the hydrolysis of oxidized acyl chains from phosphatidylcholine-based oxidized phospholipids and oxidized free fatty acids [34][35][36]. It has been demonstrated that HDL-associated platelet-activating factor acetylhydrolase (PAF-AH) hampers the production and limits the activity of mildly oxidized low-density lipoprotein since it facilitates the hydrolysis of active oxidized phospholipids to lysolipids, which in consequence results in the removal of biologically active lipids in these lipoproteins [37].…”

Dietary Patterns and Health Outcomes among African American Maintenance Hemodialysis Patients

“…The hiSSB group tended to have higher levels of CRP, IL-18, and MCP-1, although the difference in these inflammatory markers between the loSSB and hiSSB groups was not significant. Given that low grade inflammation may play a role as both a cause and consequence of low HDL-C levels [47,48], and higher HDL-C levels may act as a buffer against low-grade inflammation [49][50][51], the lower levels of HDL-C observed in the hiSSB group may have been a consequence of proinflammatory factors modulated by a high sugar dietary pattern.…”

Potential of Lipoprotein-Based Nanoparticulate Formulations for the Treatment of Eye Diseases

“…[47][48][49][50] The uptake of oxidized LDL by macrophages via scavenger receptors transforms them into foam cells, which is a marker of atherosclerosis. 51) HDL is responsible for the transport of cholesterol from cells back to the liver and exerts a protective effect against atherosclerosis. It acts as an antioxidative agent, protecting against the generation of oxidized lipids by the action of redox-active Met residues of apoA-I or receiving lipid hydroperoxides from oxidized LDL via SR-BI.…”