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      Phosphatidylcholine and phosphatidylethanolamine plasmalogens in lipid loaded human macrophages

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          Abstract

          Background

          Plasmalogens are either phosphatidylcholine (PC P) or phosphatidylethanolamine (PE P) glycerophospholipids containing a vinyl ether moiety in sn-1-position and an esterified fatty acid in sn-2 position. Multiple functions have been proposed, including reservoir of precursors for inflammatory mediators, modulation of membrane fluidity, and anti-oxidative properties. They could therefore play a role under conditions of metabolic stress. Especially enzymatically modified LDL (eLDL) and oxidatively modified LDL (oxLDL) represent modifications of LDL that are taken up by macrophages in atherosclerotic plaques. The aim of this study was to analyze plasmalogen related effects of eLDL and oxLDL in human monocyte derived macrophages, as well as the effects of HDL 3 mediated deloading.

          Methods

          Elutriated monocytes from nine healthy donors were differentiated in vitro for four days. Macrophages were then loaded with native LDL, eLDL and oxLDL for 24h and subsequently deloaded with HDL 3 for another 24h. Lipidomic and transcriptomic profiles were obtained.

          Results

          Loading of macrophages with eLDL and oxLDL led to a transient but strong elevation of lysophosphatidylcholine (LPC) most likely through direct uptake. Only eLDL induced increased levels of total PC, presumably through an induction of PC synthesis. On the other hand treatment with oxLDL led to a significant increase in PC P. Analysis of individual lipid species showed lipoprotein and saturation specific effects for LPC, PC P and PE P species. Membrane fluidity was decreased by the large amount of FC contained in the lipoproteins, as indicated by a lower PC to FC ratio after lipoprotein loading. In contrast the observed changes in the saturated to mono-unsaturated fatty acid (SFA to MUFA) and saturated to poly-unsaturated fatty acid (SFA to PUFA) ratios in PE P could represent a cellular reaction to counteract this effect by producing more fluid membranes. Transcriptomic analysis showed considerable differences between eLDL and oxLDL treated macrophages. As a common feature of both lipoproteins we detected a strong downregulation of pathways for endogenous lipid synthesis as well as for exogenous lipid uptake. Deloading with HDL 3 had only minor effects on total lipid class as well as on individual lipid species levels, most of the time not reaching significance. Interestingly treatment with HDL 3 had no effect on membrane fluidity under these conditions, although incubation with HDL 3 was partially able to counteract the oxLDL induced transcriptomic effects. To investigate the functional effect of lipoprotein treatment on macrophage polarization we performed surface marker flow cytometry. Under our experimental conditions oxLDL was able to partially shift the surface marker pattern towards a pro-inflammatory M1-like phenotype. This is consistent with the consumption of arachidonic acid containing PE P species in oxLDL treated cells, presumably for the synthesis of inflammatory mediators.

          Summary

          Our findings provide novel data on the lipoprotein induced, lipidomic and transcriptomic changes in macrophages. This can help us better understand the development of metabolic, inflammatory diseases as well as improve our background knowledge on lipid biomarkers in serum.

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          Most cited references48

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          Atherosclerosis. the road ahead.

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            Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome.

            NLRP3 forms an inflammasome with its adaptor ASC, and its excessive activation can cause inflammatory diseases. However, little is known about the mechanisms that control assembly of the inflammasome complex. Here we show that microtubules mediated assembly of the NLRP3 inflammasome. Inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme NAD(+), which in turn inactivated the NAD(+)-dependent α-tubulin deacetylase sirtuin 2; this resulted in the accumulation of acetylated α-tubulin. Acetylated α-tubulin mediated the dynein-dependent transport of mitochondria and subsequent apposition of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Therefore, in addition to direct activation of NLRP3, the creation of optimal sites for signal transduction by microtubules is required for activation of the entire NLRP3 inflammasome.
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              Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues.

              Using a sensitive Northern blot hybridization technique, gene expression of superoxide dismutase (SOD), catalase, and glutathione peroxidase was studied in pancreatic islets and for comparison in various other mouse tissues (liver, kidney, brain, lung, skeletal muscle, heart muscle, adrenal gland, and pituitary gland). Gene expression of the antioxidant enzymes was usually in the range of +/- 50% of that in the liver. Only in pancreatic islets gene expression was substantially lower. The levels of the cytoplasmic Cu/Zn SOD and the mitochondrial Mn SOD gene expression were in the range of 30-40% of those in the liver. Glutathione peroxidase gene expression was 15%, and catalase gene expression was not at all detectable in pancreatic islets. These low levels of antioxidant enzyme gene expression may provide an explanation for the extraordinary sensitivity of pancreatic beta cells towards cytotoxic damage by diabetogenic compounds and during the development of human and animal diabetes.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Methodology
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Resources
                Role: Data curationRole: Formal analysisRole: Software
                Role: Data curationRole: Methodology
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 October 2018
                2018
                : 13
                : 10
                : e0205706
                Affiliations
                [001]Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, Regensburg, Germany
                Universita degli Studi di Padova, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                [¤a]

                Current address: Beckman Coulter GmbH, Berlin, Germany

                [¤b]

                Current address: Thermo Fisher Scientific, Regensburg, Germany

                Author information
                http://orcid.org/0000-0002-3365-9579
                Article
                PONE-D-18-18159
                10.1371/journal.pone.0205706
                6181407
                30308051
                d8144dd6-3249-4f24-8d73-0ce9f0e83b54
                © 2018 Wallner et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 June 2018
                : 28 September 2018
                Page count
                Figures: 7, Tables: 0, Pages: 21
                Funding
                Funded by: European Union FP7/Lipidomic Net
                Award ID: 202272
                Award Recipient : Gerd Schmitz
                Funded by: Bundesministerium für Bildung und Forschung (DE)
                Award ID: FKZ01KU1216J
                Award Recipient : Gerd Schmitz
                The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 202272, IP-Project LipidomicNet to GS. The results of this publication were partly funded by the Federal Ministry of Education and Research under the Project Number FKZ01KU1216J (Deutsches Epigenom Programm, DEEP) to GS.
                Categories
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                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
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                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Biochemistry
                Lipids
                Biology and Life Sciences
                Biochemistry
                Proteins
                Lipoproteins
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Transcriptome Analysis
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                Biochemistry
                Lipids
                Fatty Acids
                Biology and Life Sciences
                Biochemistry
                Lipids
                Lipid Metabolism
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Lipid Metabolism
                Biology and Life Sciences
                Biochemistry
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                All relevant data are within the paper and its Supporting Information files.

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