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Lipid Signaling and Metabolism in Inflammation-Associated Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 18388

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Prof. Dr. Hartmut Kühn

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Department of Biochemistry, Charité – University Medicine Berlin, Charitéplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany
Interests: lipid metabolism; catalytic mechanism; eicosanoids; lipoxygenase; leukotrienes; selenocysteine
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Dear Colleagues,

When the human body is challenged by pathogens, cell damage or irritants, a complex counteracting response of the immune system is initiated. This response is aimed at eliminating the inflammatory stimuli and at reestablishing tissue homeostasis. Although the inflammatory response is beneficial for the entire body, it involves locally destructive processes leading to cell injury and tissue damage. During the phase of inflammatory resolution (healing phase) the inflamed tissue is cleaned up and the original tissue structure is reestablished. In principle, inflammation can affect all organs, and thus can impact organ-specific functions. However, despite tissue-specific differences, the basic mechanisms are always similar. In most cases, inflammation starts as an acute process which either heals completely (restitution ad integrum) or turns into chronic inflammation when the healing process is incomplete. A key event in acute inflammation is the local activation of immune cells, particularly of neutrophils and pro-inflammatory M1 macrophages. Lymphocytes (B- and T- cells) are rare in acutely inflamed tissue, but occur more frequently in chronic inflammation. Inflammatory cells are attracted by pro-inflammatory signals produced in inflamed tissue. They leave the vasculature and actively migrate towards the center of inflammation following the gradient of pro-inflammatory mediators. Acute inflammation and inflammatory resolution are characterized by specific profiles of lipid mediators, which are biosynthesized by different cell types. It is the major aim of this Special Issue to summarize our current knowledge on lipid signaling and lipid metabolism in all types of inflammation-associated diseases, which includes the biosynthesis and modes of action of pro- and anti-inflammatory lipid mediators.

Prof. Dr. Hartmut Kühn
Guest Editor

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Keywords

prostaglandins
leukotrienes
lipoxins
resolvins/maresins
hepoxilins
eoxins
cyclooxygenas
lipoxygenase
cytochrome P450

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Lipid Signaling and Metabolism in Inflammation-Associated Diseases 2.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (9 papers)

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Research

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23 pages, 3728 KiB

Open AccessArticle

Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models

by Marjann Schäfer, Florian Reisch, Dominika Labuz, Halina Machelska, Sabine Stehling, Gerhard P. Püschel, Michael Rothe, Dagmar Heydeck and Hartmut Kuhn

Int. J. Mol. Sci. 2023, 24(13), 11034; https://doi.org/10.3390/ijms241311034 - 3 Jul 2023

Cited by 3 | Viewed by 1501

Abstract

Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15b (Alox8). This functional difference impacts the biosynthetic capacity of the two enzymes for creating pro- and anti-inflammatory eicosanoids. To explore the functional consequences of the humanization of the reaction specificity of mouse Alox15b in vivo, we tested Alox15b knock-in mice that express the arachidonic acid 15-lipoxygenating Tyr603Asp and His604Val double mutant of Alox15b, instead of the arachidonic acid 8-lipoxygenating wildtype enzyme, in two different animal inflammation models. In the dextran sodium sulfate-induced colitis model, female Alox15b-KI mice lost significantly more bodyweight during the acute phase of inflammation and recovered less rapidly during the resolution phase. Although we observed significant differences in the colonic levels of selected pro- and anti-inflammatory eicosanoids during the time-course of inflammation, there were no differences between the two genotypes at any time-point of the disease. In Freund’s complete adjuvant-induced paw edema model, Alox15b-KI mice were less susceptible than outbred wildtype controls, though we did not observe significant differences in pain perception (Hargreaves-test, von Frey-test) when the two genotypes were compared. our data indicate that humanization of the reaction specificity of mouse Alox15b (Alox8) sensitizes mice for dextran sodium sulfate-induced experimental colitis, but partly protects the animals in the complete Freund’s adjuvant-induced paw edema model. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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10 pages, 768 KiB

Open AccessArticle

Inhibitory Investigations of Acyl-CoA Derivatives against Human Lipoxygenase Isozymes

by Michelle Tran, Kevin Yang, Alisa Glukhova, Michael Holinstat and Theodore Holman

Int. J. Mol. Sci. 2023, 24(13), 10941; https://doi.org/10.3390/ijms241310941 - 30 Jun 2023

Cited by 2 | Viewed by 1316

Abstract

Lipid metabolism is a complex process crucial for energy production resulting in high levels of acyl-coenzyme A (acyl-CoA) molecules in the cell. Acyl-CoAs have also been implicated in inflammation, which could be possibly linked to lipoxygenase (LOX) biochemistry by the observation that an acyl-CoA was bound to human platelet 12-lipoxygenase via cryo-EM. Given that LOX isozymes play a pivotal role in inflammation, a more thorough investigation of the inhibitory effects of acyl-CoAs on lipoxygenase isozymes was judged to be warranted. Subsequently, it was determined that C18 acyl-CoA derivatives were the most potent against h12-LOX, human reticulocyte 15-LOX-1 (h15-LOX-1), and human endothelial 15-LOX-2 (h15-LOX-2), while C16 acyl-CoAs were more potent against human 5-LOX. Specifically, oleoyl-CoA (18:1) was most potent against h12-LOX (IC₅₀ = 32 μM) and h15-LOX-2 (IC₅₀ = 0.62 μM), stearoyl-CoA against h15-LOX-1 (IC₅₀ = 4.2 μM), and palmitoleoyl-CoA against h5-LOX (IC₅₀ = 2.0 μM). The inhibition of h15-LOX-2 by oleoyl-CoA was further determined to be allosteric inhibition with a K_i of 82 +/− 70 nM, an α of 3.2 +/− 1, a β of 0.30 +/− 0.07, and a β/α = 0.09. Interestingly, linoleoyl-CoA (18:2) was a weak inhibitor against h5-LOX, h12-LOX, and h15-LOX-1 but a rapid substrate for h15-LOX-1, with comparable kinetic rates to free linoleic acid (k_cat = 7.5 +/− 0.4 s⁻¹, k_cat/K_M = 0.62 +/− 0.1 µM⁻¹s⁻¹). Additionally, it was determined that methylated fatty acids were not substrates but rather weak inhibitors. These findings imply a greater role for acyl-CoAs in the regulation of LOX activity in the cell, either through inhibition of novel oxylipin species or as a novel source of oxylipin-CoAs. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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14 pages, 2029 KiB

Open AccessArticle

The Sizes and Composition of HDL-Cholesterol Are Significantly Associated with Inflammation in Rheumatoid Arthritis Patients

by Ching-Kun Chang, En-Pei Isabel Chiang, Kuang-Hsi Chang, Kuo-Tung Tang, Po-Ku Chen, Hei-Tung Yip, Chu-Huang Chen and Der-Yuan Chen

Int. J. Mol. Sci. 2023, 24(13), 10645; https://doi.org/10.3390/ijms241310645 - 26 Jun 2023

Cited by 4 | Viewed by 2144

Abstract

Rheumatoid arthritis (RA), a chronic inflammatory disease, carries a significant burden of atherosclerotic cardiovascular diseases (ASCVD). With their heterogeneous composition, high-density lipoprotein (HDL) particles have varied athero-protective properties, and some may even increase ASCVD risk. In this prospective and cross-sectional study, we aimed to examine the relationship between HDL sizes/metabolites and inflammation in RA. Using ¹H-NMR-based lipid/metabolomics, differential HDL-related metabolites were identified between RA patients and healthy control (HC) subjects and between RA patients with and without anti-citrullinated peptide antibodies (ACPA). The correlation between the discriminative HDL-related metabolites and C-reactive protein (CRP) was evaluated in RA patients. RA patients demonstrated higher particle number, lipids, cholesterol, cholesterol ester, free cholesterol, and phospholipids in large/very large-sized HDLs. ACPA-positive patients had higher L-HDL-C and L-HDL-CE but lower small-/medium-sized HDL-TG levels than ACPA-negative patients. An inverse correlation was found between CRP levels and small-sized HDLs. Janus kinase inhibitor treatment was associated with increased serum small-sized HDL-related metabolites and decreased CRP levels. We are the first to reveal the significant associations between RA inflammation and HDL sizes/metabolites. A potential link between ACPA positivity and changes in serum levels of HDL-related metabolites was also observed in RA patients. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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20 pages, 9424 KiB

Open AccessArticle

Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A₄ Hydrolase

by Tarvi Teder, Stefanie König, Rajkumar Singh, Bengt Samuelsson, Oliver Werz, Ulrike Garscha and Jesper Z. Haeggström

Int. J. Mol. Sci. 2023, 24(8), 7539; https://doi.org/10.3390/ijms24087539 - 19 Apr 2023

Cited by 1 | Viewed by 1946

Abstract

The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A₄ epoxide which is converted to a chemotactic leukotriene B₄ (LTB₄) by leukotriene A₄ hydrolase (LTA₄H). In addition, LTA₄H possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTA₄H, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTA₄H at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTA₄H with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB₄ and can potentially be used as modulators of inflammatory response by the 5-LOX pathway. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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29 pages, 20570 KiB

Open AccessArticle

Hydroperoxidation of Docosahexaenoic Acid by Human ALOX12 and pigALOX15-mini-LOX

by Miquel Canyelles-Niño, Àngels González-Lafont and José M. Lluch

Int. J. Mol. Sci. 2023, 24(7), 6064; https://doi.org/10.3390/ijms24076064 - 23 Mar 2023

Cited by 2 | Viewed by 1898

Abstract

Human lipoxygenase 12 (hALOX12) catalyzes the conversion of docosahexaenoic acid (DHA) into mainly 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid (14S-H(p)DHA). This hydroperoxidation reaction is followed by an epoxidation and hydrolysis process that finally leads to maresin 1 (MaR1), a potent bioactive specialized pro-resolving mediator (SPM) in chronic inflammation resolution. By combining docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations, we have computed the potential energy profile of DHA hydroperoxidation in the active site of hALOX12. Our results describe the structural evolution of the molecular system at each step of this catalytic reaction pathway. Noteworthy, the required stereospecificity of the reaction leading to MaR1 is explained by the configurations adopted by DHA bound to hALOX12, along with the stereochemistry of the pentadienyl radical formed after the first step of the mechanism. In pig lipoxygenase 15 (pigALOX15-mini-LOX), our calculations suggest that 14S-H(p)DHA can be formed, but with a stereochemistry that is inadequate for MaR1 biosynthesis. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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24 pages, 2880 KiB

Open AccessArticle

Functional Characterization of Transgenic Mice Overexpressing Human 15-Lipoxygenase-1 (ALOX15) under the Control of the aP2 Promoter

by Dagmar Heydeck, Christoph Ufer, Kumar R. Kakularam, Michael Rothe, Thomas Liehr, Philippe Poulain and Hartmut Kuhn

Int. J. Mol. Sci. 2023, 24(5), 4815; https://doi.org/10.3390/ijms24054815 - 2 Mar 2023

Cited by 3 | Viewed by 2619

Abstract

Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory, hyperproliferative, neurodegenerative, and metabolic diseases, but the physiological function of ALOX15 still remains a matter of discussion. To contribute to this discussion, we created transgenic mice (aP2-ALOX15 mice) expressing human ALOX15 under the control of the aP2 (adipocyte fatty acid binding protein 2) promoter, which directs expression of the transgene to mesenchymal cells. Fluorescence in situ hybridization and whole-genome sequencing indicated transgene insertion into the E1-2 region of chromosome 2. The transgene was highly expressed in adipocytes, bone marrow cells, and peritoneal macrophages, and ex vivo activity assays proved the catalytic activity of the transgenic enzyme. LC-MS/MS-based plasma oxylipidome analyses of the aP2-ALOX15 mice suggested in vivo activity of the transgenic enzyme. The aP2-ALOX15 mice were viable, could reproduce normally, and did not show major phenotypic alterations when compared with wildtype control animals. However, they exhibited gender-specific differences with wildtype controls when their body-weight kinetics were evaluated during adolescence and early adulthood. The aP2-ALOX15 mice characterized here can now be used for gain-of-function studies evaluating the biological role of ALOX15 in adipose tissue and hematopoietic cells. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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20 pages, 4482 KiB

Open AccessArticle

Functional Characterization of Novel Bony Fish Lipoxygenase Isoforms and Their Possible Involvement in Inflammation

by Sophie Roigas, Dagmar Heydeck and Hartmut Kuhn

Int. J. Mol. Sci. 2022, 23(24), 16026; https://doi.org/10.3390/ijms232416026 - 16 Dec 2022

Cited by 2 | Viewed by 1411

Abstract

Eicosanoids and related compounds are pleiotropic lipid mediators, which are biosynthesized in mammals via three distinct metabolic pathways (cyclooxygenase pathway, lipoxygenase pathway, epoxygenase pathway). These mediators have been implicated in the pathogenesis of inflammatory diseases and drugs interfering with eicosanoid signaling are currently available as antiphlogistics. Eicosanoid biosynthesis has well been explored in mammals including men, but much less detailed information is currently available on eicosanoid biosynthesis in other vertebrates including bony fish. There are a few reports in the literature describing the expression of arachidonic acid lipoxygenases (ALOX isoforms) in several bony fish species but except for two zebrafish ALOX-isoforms (zfALOX1 and zfALOX2) bony fish eicosanoid biosynthesizing enzymes have not been characterized. To fill this gap and to explore the possible roles of ALOX15 orthologs in bony fish inflammation we cloned and expressed putative ALOX15 orthologs from three different bony fish species (N. furzeri, P. nyererei, S. formosus) as recombinant N-terminal his-tag fusion proteins and characterized the corresponding enzymes with respect to their catalytic properties (temperature-dependence, activation energy, pH-dependence, substrate affinity and substrate specificity with different polyenoic fatty acids). Furthermore, we identified the chemical structure of the dominant oxygenation products formed by the recombinant enzymes from different free fatty acids and from more complex lipid substrates. Taken together, our data indicate that functional ALOX isoforms occur in bony fish but that their catalytic properties are different from those of mammalian enzymes. The possible roles of these ALOX-isoforms in bony fish inflammation are discussed. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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19 pages, 1978 KiB

Open AccessArticle

The FKBP51 Inhibitor SAFit2 Restores the Pain-Relieving C16 Dihydroceramide after Nerve Injury

by Saskia Wedel, Lisa Hahnefeld, Mohamad Wessam Alnouri, Stefan Offermanns, Felix Hausch, Gerd Geisslinger and Marco Sisignano

Int. J. Mol. Sci. 2022, 23(22), 14274; https://doi.org/10.3390/ijms232214274 - 17 Nov 2022

Cited by 4 | Viewed by 2281

Abstract

Neuropathic pain is a pathological pain state with a broad symptom scope that affects patients after nerve injuries, but it can also arise after infections or exposure to toxic substances. Current treatment possibilities are still limited because of the low efficacy and severe adverse effects of available therapeutics, highlighting an emerging need for novel analgesics and for a detailed understanding of the pathophysiological alterations in the onset and maintenance of neuropathic pain. Here, we show that the novel and highly specific FKBP51 inhibitor SAFit2 restores lipid signaling and metabolism in nervous tissue after nerve injury. More specifically, we identify that SAFit2 restores the levels of the C16 dihydroceramide, which significantly reduces the sensitization of the pain-mediating TRPV1 channel and subsequently the secretion of the pro-inflammatory neuropeptide CGRP in primary sensory neurons. Furthermore, we show that the C16 dihydroceramide is capable of reducing acute thermal hypersensitivity in a capsaicin mouse model. In conclusion, we report for the first time the C16 dihydroceramide as a novel and crucial lipid mediator in the context of neuropathic pain as it has analgesic properties, contributing to the pain-relieving properties of SAFit2. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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Review

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13 pages, 1184 KiB

Open AccessReview

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

by Fiorella Tonello

Int. J. Mol. Sci. 2023, 24(2), 1579; https://doi.org/10.3390/ijms24021579 - 13 Jan 2023

Cited by 2 | Viewed by 2444

Abstract

Secreted phospholipases of type A2 (sPLA2s) are proteins of 14–16 kDa present in mammals in different forms and at different body sites. They are involved in lipid transformation processes, and consequently in various immune, inflammatory, and metabolic processes. sPLA2s are also major components of snake venoms, endowed with various toxic and pharmacological properties. The activity of sPLA2s is not limited to the enzymatic one but, through interaction with different types of molecules, they exert other activities that are still little known and explored, both outside and inside the cells, as they can be endocytosed. The aim of this review is to analyze three features of sPLA2s, yet under-explored, knowledge of which could be crucial to understanding the activity of these proteins. The first feature is their disulphide bridge pattern, which has always been considered immutable and necessary for their stability, but which might instead be modulable. The second characteristic is their ability to undergo various post-translational modifications that would control their interaction with other molecules. The third feature is their ability to participate in active molecular condensates both on the surface and within the cell. Finally, the implications of these features in the design of anti-inflammatory drugs are discussed. Full article

(This article belongs to the Special Issue Lipid Signaling and Metabolism in Inflammation-Associated Diseases)

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