Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

Abstract

Ultraviolet light radiation (UVR) has profound effects upon human skin. Yet, the exact targets for UVR are unclear. Inasmuch as UVR is a known pro-oxidative stressor, one potential target for UVR could be oxidatively modified glycerophosphocholines (GPC). Importantly, recent studies demonstrate that these oxidized GPCs (ox-GPC) are potent agonists for the platelet-activating factor receptor and peroxisome proliferator-activated receptor gamma. This review discusses these new biologically active lipids and their down-stream receptor targets that provide a unique system of biosensors for detecting and responding to UVR photo-oxidation.

Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts

“…When this reaction is performed in the presence of PAPC vesicles, bioactive oxidized phospholipids are formed, and these can also be isolated from cultured fibroblasts that were exposed to PBS supplemented with Rose Bengal and exposed to visible light [13]. A large number of oxidation products is formed upon in-vitro UVA irradiation of phospholipids containing arachidonic-or docosahexaenoic acid, confirming that the immediate generation of many bioactive oxidation products of PL that we and others observed in the skin after UVR does not necessarily require UV-induced enzymatic activity [50][51][52]. The observed increase in 8-isoprostane in the supernatants of Nrf2 deficient and supplemented fibroblasts is not only a good independent indicator of enhanced oxidative stress in these cells but also suggests that synthesis and secretion of 8-isoprostane (which is discarded via the urine) is a strategy of cells to reduce the burden that PUFA pose under oxidative stress.…”

“…Several prostaglandins and enzymatic n-3 PUFA metabolites are regulators of the PPAR transcriptional coactivators which regulate skin homeostasis and UV responses [62], and PPARG apparently counteracts UVB induced inflammation [63]. Upon UV exposure, the PPARG agonist 1-alkyl-2-azelaoyl-PC can form non-enzymatically, is active when still esterified to the PL [52] but can also be cleaved by PLA2 to release free azelaic acid [64]. In this study we have detected 1-acyl-2azelaoyl-PC to be formed by UV and increased upon DHA supplementation.…”

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

“…A second mechanism for Ox-GPC generation appears to be the direct absorption of UVB irradiation by lipids and is immediate (28,29,40). Although GPCs do not absorb light in the UVB range, we have shown that Ox-GPCs do absorb in this range (29). Thus, small amounts of Ox-GPCs that are found in cells at any one time can serve as targets for UVB irradiation.…”

“…First, UVB irradiation can generate the delayed production of ROS through a process involving NADPH and the epidermal growth factor receptor (40,62,63). A second mechanism for Ox-GPC generation appears to be the direct absorption of UVB irradiation by lipids and is immediate (28,29,40). Although GPCs do not absorb light in the UVB range, we have shown that Ox-GPCs do absorb in this range (29).…”

“…PAF-R agonists such as sn-2 butanoyl, oxovaleroyl, and glutaroyl GPC species as well as PAF itself are produced nonenzymatically via free radical-mediated oxidation of sn-2 polyunsaturated fatty acyl glycerophosphocholines (27)(28)(29)47). Because XPA-deficient cells have decreased antioxidant defenses (11-14), we next tested the hypothesis that ROS generation was important to the mechanism for the enhanced PAF-R agonists produced in response to UVB irradiation in the XPA-deficient cells.…”