Biologically Active Oxidized Phospholipids

Abstract

Oxidants and free radicals are deleterious in many ways, and organisms employ numerous approaches to block their production or limit their damage. Hydrogen atoms adjacent to olefinic bonds are susceptible to oxidative attack and those between unconjugated olefinic bonds especially so. Lipids are a rich source of these bonds and so are a primary target for oxidative reactions. Lipid oxidation is problematic as the many oxidative chemical reactions are not controlled and constrained by enzymes and may show exponential reaction rates, and some of the products of the attack are highly reactive species that modify proteins and DNA. This review summarizes current information about another outcome of the uncontrolled attack on cellular and circulating phospholipids, the generation of potent biologically active compounds that activate components of the immune and inflammatory systems.The biologically active species discussed here include oxidized phosphatidylcholines with biologic activity similar to platelet-activating factor (PAF), 1 oxidized phosphatidylcholines that stimulate responses through ways other than the PAF receptor, and the lysophosphatidylcholines that result from the enzymatic metabolism of these modified phospholipids. Oxidation products that mimic the properties of a wide variety of arachidonate metabolites are discussed in a separate review in this series (FitzGerald et al. (85)), as is a study of the effects of cholesterol oxidation (Chisolm et al. (86)). We will briefly mention the role of PAF acetylhydrolase in the catabolism of oxidized phospholipids. With the structures of some biologically active oxidation products deciphered, there is physical evidence to show that oxidatively modified phospholipids accumulate in vivo. This suggests that potent biologic mediators can arise from uncontrolled chemical reactions when the antioxidant defenses of the organism are overwhelmed. One area where such newly formed species subvert physiologic events is atherogenesis, but exposure to cigarette smoke, reperfusion injury, and stroke are also likely candidates for inappropriate events initiated or propagated by biologically active oxidized phospholipids. Lipid OxidationOxidative reactions of free fatty acids have been defined (e.g. Refs. 1-3), and oxidation of fatty acyl residues esterified in phospholipids appears to proceed in a similar fashion. The initial oxidative attack on polyunsaturated fatty acids generates alkyl radicals and then with the addition of oxygen, alkoxy radicals and peroxides. Arachidonate when oxidized enzymatically generates hydroperoxyeicosatetraenoates, hydroxyeicosatetraenoates, prostaglandins, and leukotrienes. A larger series of stereo and positional isomers known as isoprostanes, isothromboxanes, and isoleukotrienes (4, 5) is produced when arachidonate is nonenzymatically oxidized by a series of competing chemical reactions.

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists

“…Similarly, oxidized LDL in the circulation (42,50) or in atherosclerotic plaques (43) also contains fragmented and oxidatively modified phospholipids (26,40,43). Some of these are agonists for the PAF receptor (27,51). Here we show that others are high affinity ligands and activators of PPAR␥.…”

Platelet-activating Factor Acetylhydrolase, and Not Paraoxonase-1, Is the Oxidized Phospholipid Hydrolase of High Density Lipoprotein Particles

“…Oxidized LDL-We purified PON1 as described (2,33) and assayed its hydrolysis of PAF or the PAF-like phospholipids produced during LDL oxidation (19,22,23). We chose a bioassay to examine hydrolysis because inactivation of these lipid mediators is the important outcome, and because the extreme potency of these mediators makes assays other than biologic ones impractical.…”

“…Oxidized lipoprotein particles contain pro-inflammatory lipid mediators that include ones that functionally mimic the potent phospholipid mediator platelet-activating factor (PAF) (19). PAF initiates physiologic inflammation and is active at picomolar levels.…”

Epidermal Peroxisome Proliferator-activated Receptor γ as a Target for Ultraviolet B Radiation

“…9 -11). For example, oxidation of low density lipoprotein generates a series of lipid inflammatory mediators among which some fragmented phospholipids could potently activate inflammatory cells through the platelet-activating factor receptor (12,13). Davies et al (14) showed that oxidatively modified phosphatidylcholines from oxidized low density lipoprotein are high affinity ligands and agonists for peroxisome proliferator-activated receptor ␥ (PPAR␥).…”