Phospholipase A2 catalysis and lipid mediator lipidomics

Mouchlis, Varnavas D.; Dennis, Edward A.

doi:10.1016/j.bbalip.2018.08.010

Cited by 107 publications

(78 citation statements)

References 67 publications

(88 reference statements)

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“…Oxylipins are lipid mediators synthesized by polyunsaturated fatty acid (PUFA) oxidation in all tissues, including the spleen, via enzymatic and nonenzymatic pathways. The current model describes the release of free PUFA from phospholipid (PL) through the action of phospholipase A 2 and then oxygenation by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes to form oxylipins (Adler et al, ; Gabbs et al, ; Mouchlis and Dennis, ; Tourdot et al, ). This model predicts that dietary supplementation with a particular PUFA will increase its presence in cellular membranes (Mantzioris et al, ), giving it a competitive advantage for cleavage and conversion to oxylipins (Ostermann and Schebb, ).…”

Section: Introductionmentioning

confidence: 99%

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex

Pauls

Ragheb

Winter

et al. 2020

Lipids

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As the largest secondary lymphoid organ, the spleen plays an important role in immune responses. The role of arachidonic acid (ARA) and its 20-carbon eicosanoids in modulating immune function has long been of interest. However, recent advances have enabled the identification of numerous other n-6 and n-3 polyunsaturated fatty acid (PUFA)-derived oxylipins. Here, we investigate the effects of diet and sex on the spleen nonesterified oxylipin profiles and phospholipid and neutral lipid PUFA composition in Sprague-Dawley rats supplemented with oils rich in α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or linoleic acid. Dietary ALA, EPA, and DHA resulted in lower levels of ARA and ARA oxylipins. Oxylipins derived from other n-6 PUFA were also reduced despite no or opposite effect on their PUFA levels. Each diet also resulted in higher levels of oxylipins almost exclusively derived from the supplemented PUFA, despite PUFA in the same biosynthetic pathway also often being increased. Further, while oxylipin differences often reflected changes to phospholipid PUFA, there were instances where they corresponded more closely to changes in neutral lipid PUFA. With respect to sex effects, >50% of lipoxygenase ARA-derived oxylipins were higher in males in at least one diet group, while multiple DHA oxylipins were lower in males only in rats provided the DHA diet. This fundamental description of oxylipin composition in the spleen, including the influence of diet and sex and the relationship to PUFA composition, will help inform future studies examining the functions of these oxylipins under physiological and pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex

Pauls

Ragheb

Winter

et al. 2020

Lipids

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“…Interfacial activation of certain enzymes involves conformational changes or displacement of a lid which covers the active or catalytical site slot, while the others become activated via yet unidentified mechanisms 28 . It is generally in common that the membrane or a hydrophobic surface acts as an allosteric ligand, shifting the conformation of a PLA 2 from the closed form in water to the open form on the surface of the membrane or hydrophobic aggregate 29 . This process enables the enzyme to bind a phospholipid molecule in the active site (ES•M), where it is converted into product (EP•M) 29 .…”

Section: Discussionmentioning

confidence: 99%

Active site competition is the mechanism for the inhibition of lipoprotein-associated phospholipase A2 by detergent micelles or lipoproteins and for the efficacy reduction of darapladib

Zhuo

Yuan

2020

Sci Rep

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Lipoprotein associated phospholipase A2 (Lp-PLA2) has been characterized for its interfacial activation as well as inhibition by detergent micelles and lipoprotein particles. The enzyme has been shown to bind on the surfaces of hydrophobic aggregates, such as detergent micelles, lipoprotein particles and even polystyrene latex nanobeads. Binding to hydrophobic aggregates stimulates the activity of Lp-PLA2 but may not be the necessary step for catalysis. However, at higher concentrations, detergent micelles, latex nanobeads or lipoprotein particles inhibit Lp-PLA2 possibly by blocking the access of substrates to the active site. The competition mechanism also blocks inhibitors such as darapladib binding to Lp-PLA2 and reduces the efficacy of the drug. Darapladib has very low solubility and mainly exists in solutions as complexes with detergents or lipoprotein particles. The inhibition of Lp-PLA2 by darapladib is dependent on many factors such as concentrations of detergents or lipoproteins, incubation time, as well as the order of mixing reaction components. The in vitro Lp-PLA2 activity assays used in clinical studies may not accurately reflect the residual Lp-PLA2 activity in vivo. Darapladib has been found mainly bound on HDL and albumin when it is incubated with human serum. However, Lp-PLA2 is more sensitive to darapladib when bound on LDL and relatively resistant to darapladib when bound on HDL. Therefore, high cholesterol levels may decrease the efficacy of darapladip and cause the drug to be less effective in high risk patients. Our study will help to design better inhibitors for Lp-PLA2. The discoveries also contribute to understanding the mechanism of interfacial activation and inhibition for Lp-PLA2 and provide a new concept for researchers in building better kinetic model for interfacial enzymes.

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“…A fatty acid is esterified to the glycerol backbone in the sn -2 position of phospholipids, and in the sn -1 position there is an ester, ether, or vinyl ether linkage to a fatty acid, fatty alcohol, or fatty aldehyde residue, respectively. Phospholipase A 2 (PLA 2 ) enzymes hydrolyze the phospholipid sn -2 ester bond to yield a free fatty acid and a 2-lysophospholipid as products [ 1 , 2 ]. The PLA 2 superfamily consists of at least 16 groups of structurally and functionally diverse enzymes that include secreted (sPLA 2 ), cytosolic (cPLA 2 ), calcium-independent (iPLA 2 ), lipoprotein-associated (Lp-PLA 2 ), and adipose-PLA 2 (AdPLA).…”

Section: Introductionmentioning

confidence: 99%

“…The PLA 2 superfamily consists of at least 16 groups of structurally and functionally diverse enzymes that include secreted (sPLA 2 ), cytosolic (cPLA 2 ), calcium-independent (iPLA 2 ), lipoprotein-associated (Lp-PLA 2 ), and adipose-PLA 2 (AdPLA). These enzymes play central roles in cellular lipid metabolism and signaling [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells

et al. 2020

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To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.

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Phospholipase A2 catalysis and lipid mediator lipidomics

Cited by 107 publications

References 67 publications

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex

Active site competition is the mechanism for the inhibition of lipoprotein-associated phospholipase A2 by detergent micelles or lipoproteins and for the efficacy reduction of darapladib

Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells

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