Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

Abstract

Oxidized low-density lipoprotein (OxLDL), which contains hundreds of different oxidized lipid molecules, is a hallmark of hyperlipidemia and atherosclerosis. The same oxidized lipids found in OxLDL are also formed in apoptotic cells, and are present in tissues as well as in the circulation under pathological conditions. In many disease contexts, oxidized lipids constitute damage signals, or patterns, that activate pattern-recognition receptors and significantly contribute to inflammation. This article reviews recent discoveries and emerging trends in the field of oxidized lipids and regulation of inflammation, focusing on oxidation products of polyunsaturated fatty acids esterified into cholesteryl esters and phospholipids. The paper highlights context-dependent activation and biased agonism of TLR4 and the NLRP3 inflammasome, among other signaling pathways activated by oxidized lipids.

Oxidized low‐density lipoprotein in inflammation‐driven thrombosis

“…LDL is a complex lipoprotein containing different lipid species, including triglycerides, phospholipids, and free and esterified cholesterol. Both enzymatic and nonenzymatic mechanisms have been described that result in the oxidation of both the phospholipid and cholesterol moieties of LDL, resulting in the generation of myriads of different lipid oxidation products [22]. Oxidized cholesterol and phospholipids can in turn be hydrolyzed and release free oxidized fatty acids that decompose to malondialdehyde (MDA) and 4-hydroxy-2-nonenal, and modify LDL proteins and phospholipids.…”

“…aggregates [32] Monocyte migration [32] Monocyte adhesion [22] β 1 integrin [41] P-selectin [42] TFPI [43] Thrombomodulin [44] Metalloproteinase [46] Angiogenesis [46,47] Foam cell formation [49] Foam cell formation [57] Membrane fluidity [71] CD11b/CD18 [71] NETosis [73] Chemotaxis [51] Proliferation [52] Phenotypic switch [53] Active TF [54,55] Foam cell formation [32] THROMBO-INFLAMMATORY EFFECTS…”

A monoclonal antibody to assess oxidized cholesteryl esters associated with apoAI and apoB-100 lipoproteins in human plasma

“…Human atherosclerotic lesions contain OxCE not only in a free lipid form but also as covalent adducts to proteins (14). Based on these findings, we suggest that OxCE is a major DAMP arising in hypercholesterolemic animals and human subjects, which contributes to vascular inflammation and atherogenesis (4,15).…”

“…The chemistry of this reaction is well-described; it produces polyoxygenated OxCE, including formation of bicyclic endoperoxide and hydroperoxide groups in the acyl chain, and can be initiated by the presence of 15(S)hydroperoxyeicosatetraenoic acid (34)(35)(36). The latter is a product of 12/15LO enzymatic activity, which is considered a major factor in LDL oxidation in vivo (15,24). Hypercholesterolemic Alox15 / mice develop less atherosclerosis than the mice with functional 12/15LO (37,38) and, as we show in this work, have lower plasma levels Fig.…”

Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child

“…In addition, NAC decreased the susceptibility of LDL to oxidation [20]. Oxidized LDL reflects oxidative stress, and its concentration in plasma is related to chronic inflammation and development of several chronic diseases [20, 21]. In conclusion, we present the first in vivo study of ROS reduction by NAC treatment in a boy with triple A syndrome.…”