Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Aug 19:8:66-77.
doi: 10.1016/j.bbacli.2017.07.002. eCollection 2017 Dec.

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

Fernando Brites  1 , Maximiliano Martin  1 , Isabelle Guillas  2 , Anatol Kontush  2
Affiliations
Review

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

Fernando Brites et al. BBA Clin. .

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.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Mechanisms of LDL oxidation in the arterial wall. Upon entry in the subendothelial space LDL particles are exposed to local oxidative stress arising from the presence of cell-associated enzymes, including NADPH oxidase, lipoxygenases and myeloperoxidase, as well as from transition metal ions. Oxidants produced by these entities may oxidize LDL to different degrees. Whereas NADPH oxidase and lipoxygenases only lead to the formation of minimally oxidized LDL, myeloperoxidase and NADPH oxidase combined with NO synthase oxidize LDL extensively. The minimally oxidized LDL is predominantly characterized by the presence of oxidized lipids, whilst extensive oxidation of both protein and lipid components constitutes the hallmark of extensively oxidized LDL. Minimally oxidized LDL displays low affinity to macrophage scavenger receptors and can readily return to the bloodstream. Locally, minimally oxidized LDL induces inflammatory activation involving chemokine and cytokine production and recruitment of inflammatory cells, which in turn increases chemokine and cytokine accumulation. As a result, lipid oxidation proceeds ending in the formation of heavily oxidized and fragmented apo B. Such extensively oxidized LDL are readily taken up by macrophages via scavenger receptors leading to the formation of foam cells. LDL, low density lipoprotein; oxLDL, oxidized LDL; apo, apolipoprotein; oxPL, oxidized phospholipid; LOOH, lipid hydroperoxide.
Fig. 2
Fig. 2
Mechanisms of HDL-mediated protection against LDL oxidation in the arterial wall. HDL present in the intima space can protect LDL against oxidation by several mechanisms. HDL directly protects LDL from oxidation induced by one-electron oxidants (free radicals) and removes oxidized lipids from LDL. Altogether, these activities can decrease local concentrations of oxLDL; as a consequence, LDL can retain the capacity to re-enter the bloodstream for longer time periods, diminishing inflammatory impact of LDL oxidation. Antioxidative potential of HDL particles originates both from activities of their proteins and from lipid components. Noteworthy, HDL displays much lower protective activity (if any) against two-electron oxidants as compared to one-electron oxidants. LDL, low density lipoprotein; HDL, high density lipoprotein; oxLDL, oxidized LDL; apo, apolipoprotein; oxPL, oxidized phospholipid; LOOH, lipid hydroperoxide; PON 1, paraoxonase 1; GPX3, Glutathione selenoperoxidase 3; PAF-AH, platelet-activating factor acetyl hydrolase; PS, phophatidylserine; S1P, sphingosine-1 phosphate.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hopkins P.N. Molecular biology of atherosclerosis. Physiol. Rev. 2013;93(3):1317–1542. - PubMed
    1. Steinberg D., Witztum J.L. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2010;30(12):2311–2316. - PubMed
    1. Stocker R., Keaney J.F., Jr. Role of oxidative modifications in atherosclerosis. Physiol. Rev. 2004;84(4):1381–1478. - PubMed
    1. Simionescu M., Simionescu N. Proatherosclerotic events: pathobiochemical changes occurring in the arterial wall before monocyte migration. FASEB J. 1993;7(14):1359–1366. - PubMed
    1. Camejo G., Fager G., Rosengren B., Hurt-Camejo E., Bondjers G. Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells. J. Biol. Chem. 1993;268(19):14131–14137. - PubMed