Lipid accumulation and oxidation

An increasing amount of research has supported that low-density lipoprotein (LDL) particles trapped in the subendothelial space play a vital role in the initiation of fatty streaks and progression of fibrotic plaque in atherosclerosis (Furnkranz et al., 2005). Various inflammatory diseases such as cancer, diabetes, rheumatoid arthritis and in this case atherosclerosis, feature lipid oxidation an important pathological event (Leitinger., 2005). Lipid accumulation in the intima initiate inflammation and oxidation occurs along with inflammatory activation of cell types such as the epithelium, fibroblasts, neutrophils, monocytes and in the case of atherosclerosis, the endothelium (Birukov et al., 2013).

Formation of oxPLs

Oxidised phospholipids (OxPL) form from (poly) unsaturated diacyl- and alk(en)ylacyl glycerophospholipids by radical induced mechanisms either the oxidation of LDLs (enzymatic) or from the membranes of apoptotic cells (non-enzymatic). Enzymes such as myeloperoxidase, 12/15 lipoxygenase, phospholipase A2, sphingomyelinase and NADPH oxidase are significant enzymes involved oxidative modification (Birukov et al., 2013). The oxidation of arachidonic acid containing membrane phospholipids (LDL) results primarily inMM-LDL. OxPLs have been identified in atherosclerotic plaque and circulation (Ashraf et al., 2008).

Sterol regulatory element-binding proteins are key transcription factors involved in the modulation of genes implicated in cholesterol biosynthesis and LDL uptake. SREBP1, one of the three family members, can be activated by shear stress and TNF-α (Pastorino and Shulga, 2008) in the presence of sterols via integrins and activation is prolonged by disturbed flow. The activation of SREBP1 is a result of transcriptional activation of genes which are regulated by sterol response elements (Li et al., 2002). OxPAPC has been identified as a regulator of SREBPs (Gargalovic et al., 2006). The subsequent activation of these transcription factors results in the over-induction of lipogenic enzymes and subsequent cholesterol biosynthesis which the cell is not capable of controlling.


MM-LDL differs from highly oxidised LDL undergoing less linoleic acid oxidation and little to no protein modification. MM-LDL, unlike oxLDL is involved in monocyte recruitment and macrophage transformation (Watson et al., 1997). The formation of minimally modified LDL assists in monocyte adhesion and stimulates chemokine MCP-1 and cytokines for plaque progression. The biological activity of MM-LDL is caused by the oxidation of 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine (PAPC) which then yields fragmented 1-palmitoyl-2-(5-oxovaleroyl)- sn-glycero-phosphatidylcholine (POVPC), 1-palmitoyl-2-glutaroyl-sn-glycerophosphatidylcholine (PGPC), lysophosphatidyl choline (lyso-PC), and full length products palmitoyl-2-(5,6-epoxyisoprostane E2)-snglycero- 3-phsphocholine (PEIPC), all of which have been shown to accumulate in atherosclerotic lesions (Birukov et al., 2013).

OxPAPC signalling

Oxidized LDLs (oxLDLs) mediate the inflammatory response by activating inflammatory and oxidative stress gene expression via different signalling pathways, receptors, protein kinases and transcription factors. A negative feedback loop forms as oxidative stress induces inflammatory cytokine and chemokine production which then induce free radical production (Leonarduzzi et al., 2011).

Biological function of OxPLs

The roles of OxPLs are quite diverse but typically relate to pro-inflammatory events such as cytokine stimulation, chemokine production, cell adhesion, coagulation and platelet activation (Ashraf et al., 2008). Specifically in atherosclerosis oxPLs form foam cells and initiate fatty streaks (Greig et al., 2012) and stimulate endothelial cells to secrete chemokines MCP-1 and IL-8 and monocyte recruitment to sites of vascular injury (Birukov et al., 2013). However studies on the role of oxPAPC in monolayer permeability seem to be contradictory, reporting on both a protective and pathological effect. It is known that disruption of the endothelial barrier is a key step in atheroma formation. High concentrations of oxPAPC (50-100 μg/ml) increase endothelial disruption and permeability but low levels (5-20 μg/ml) increase barrier function, protect against LPS-induced injury and induce anti-inflammatory genes (Birukova et al., 2013). Once high concentrations of oxPAPC disrupt the endothelium, signalling mechanisms are activated (Starosta et al., 2011).


Studies are ongoing for TLR4 involvement. However it not only depends on the oxPAPC concentration but the components also. In human pulmonary artery endothelial cells (HPAECs) PEIPC enhances barrier protection whereas increased levels of fragmented products of POPC, POVPC, PGPC and lyso-PC trigger signalling mechanisms and barrier disruptive effects (Birukova et al., 2013).

Apart from lower oxPAPC concentrations and products being anti-inflammatory it also has an anti-inflammatory role inhibiting the binding of LPS to LPS-binding protein therefore blocking LPS presentation to TLR-4 thus inhibiting the NF-ĸβ pathway (Mackman et al., 2003).

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