Lipoproteins as targets and markers of lipoxidation

Abstract

Lipoproteins are essential systemic lipid transport particles, composed of apolipoproteins embedded in a phospholipid and cholesterol monolayer surrounding a cargo of diverse lipid species. Many of the lipids present are susceptible to oxidative damage by lipid peroxidation, giving rise to the formation of reactive lipid peroxidation products (rLPPs). In view of the close proximity of the protein and lipid moieties within lipoproteins, the probability of adduct formation between rLPPs and amino acid residues of the proteins, a process called lipoxidation, is high. There has been interest for many years in the biological effects of such modifications, but the field has been limited to some extent by the availability of methods to determine the sites and exact nature of such modification. More recently, the availability of a wide range of antibodies to lipoxidation products, as well as advances in analytical techniques such as liquid chromatography tandem mass spectrometry (LC-MSMS), have increased our knowledge substantially. While most work has focused on LDL, oxidation of which has long been associated with pro-inflammatory responses and atherosclerosis, some studies on HDL, VLDL and Lipoprotein(a) have also been reported. As the broader topic of LDL oxidation has been reviewed previously, this review focuses on lipoxidative modifications of lipoproteins, from the historical background through to recent advances in the field. We consider the main methods of analysis for detecting rLPP adducts on apolipoproteins, including their advantages and disadvantages, as well as the biological effects of lipoxidized lipoproteins and their potential roles in diseases.

Keywords: ApoB-100; Atherosclerosis; HDL; Immunoassays; LDL; Lipid peroxidation; Liquid chromatography mass spectrometry.

Graphical abstract

Fig. 1

Structures of the reactive lipid peroxidation products (rLPPs) reported to form adducts with lipoproteins. Note that Ne-(3-methylpyridinium) is shown as the lysine adduct form.

Fig. 2

Structures of common advanced lipoxidation end products (ALEs) or adducts detected on lipoproteins. The type of rLPP causing adduct formation is written in bold above the structure(s) and the resulting adduct names are give in plain text below. Trans-HHP-lysine is trans-N^e3-[(hept-1-enyl)-4-hexylpyridinium]lysine.

Fig. 3

The most used techniques for the analysis of lipozidized lipoproteins, and their advantages and disadvantages. TBArs, thiobarbituric acid reactive substance assay; TNBS, 2,4,6-trinitrobenzene sulfonic acid; UV, Ultraviolet; IHC, Immunohistochemistry; ELISA, enzyme-linked immunosorbent assay; LC-MS, liquid chromatography-mass spectrometry; GC-MS, Gas chromatography-mass spectrometry.

Fig. 4

Scheme of the amino acid location of several types of modifications found in different apolipoproteins. The abbreviated modifications are shown in bold and given in full as follows: CH^a,Cyclic hemiacetal adduct; FDP-Lys, N^e-(3-formyl-3, 4-dehydropiperidino)lysine (formed by MA-MA); HF, 2,3-dihydrofuran adduct; HNE, 4-Hydroxy-2-nonenal; HODA-PL, 9-hydroxy-12-oxo-10-dodecenoic acid^b; HOHA-PL^b, 4-hydroxy-7-oxo-5-heptenoic acid; HOOA-PL^b, 5-hydroxy-8-oxo-6-octenoic acid; 3-HOSCA, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al; KA^a, Ketoamide adduct; KODA-PL^b, 9-keto-12-oxo-10-dodecenoic acid; KOOA-PL^b, 5-keto-8-oxo- 6-octenoic acid; KOHA-PL^b, 4-keto-7-oxo-5-heptenoic acid; MA, Michael Addition; MP-Lys, Ne-(3-methylpyr-idinium)lysine (formed by MA-SB); OV-PL^b, 5-oxovaleric acid; ON-PL^b, 9-oxononanoic acid; POVPC, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine; PONPC, 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphocholine; SB, Schiff's base adduct. ^a CH and KA forms are indistinguishable by LC-MS. ^b These adducts were detected by aminolysis and assumed to be derived from esters of lysophospholipids. This figure was prepared using data obtained from references , , , , , .

Fig. 5

Physiological effects of lipoxidized lipoproteins, with consequences for the immune system, inflammation, apoptosis and HDL function. (1) Oxidized LDL stimulates the production of antibodies against itself and oxidized phospholipids, that can be recognized by the immune system; (2) oxLDL and MDA-LDL bind to scavenger receptors, leading to their internalization and formation of foam cells; oxPC-Lp(a) promotes the expression of IL-8 by macrophages, increasing inflammation; (3) HNE-LDL leads to apoptosis by both inhibition the ubiquitin proteasome pathway and by modification of tyrosine kinase receptors, leading to their inhibition; (4) Acrolein-HDL inhibits the increase of HDL caused by 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and HDL uptake and disassembly due to the decreased binding to the LDL receptor.