bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–11–17
thirty-two papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
  2. Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
  3. Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
  4. NK2R control of energy expenditure and feeding to treat metabolic diseases.
  5. Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization.
  6. Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes.
  7. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.
  8. Interleukin-10 inhibits important components of trained immunity in human monocytes.
  9. Preoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice.
  10. Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
  11. A glutamine metabolic switch supports erythropoiesis.
  12. H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response.
  13. Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.
  14. Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes.
  15. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.
  16. Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer.
  17. PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.
  18. Itaconate promotes an unexpected tumor immune escape mechanism.
  19. Functional identification of soluble uric acid as an endogenous inhibitor of CD38.
  20. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
  21. Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles.
  22. Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.
  23. Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
  24. Hemin promotes platelet activation and plasma membrane disintegration regulated by the subtilisin-like proprotein convertase furin.
  25. Elucidating the spatiotemporal dynamics of glucose metabolism with genetically encoded fluorescent biosensors.
  26. Nonvesicular lipid transfer drives myelin growth in the central nervous system.
  27. Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway.
  28. A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling.
  29. The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases.
  30. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
  31. Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
  32. Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.
  1. Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01323-8. [Epub ahead of print]43(11): 114972
    Cancer-associated fibroblasts maintain critical pancreatic cancer cell lipid homeostasis in the tumor microenvironment.
    Xu Han, Michelle Burrows, Laura C Kim, Jimmy P Xu, Will Vostrejs, Tran Ngoc Van Le, Carson Poltorack, Yanqing Jiang, Edna Cukierman, Ben Z Stanger, Kim A Reiss, Sydney M Shaffer, Clementina Mesaros, Brian Keith, M Celeste Simon.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with abundant cancer-associated fibroblasts (CAFs) creating hallmark desmoplasia that limits oxygen and nutrient delivery. This study explores the importance of lipid homeostasis under stress. Exogenous unsaturated lipids, rather than de novo synthesis, sustain PDAC cell viability by relieving endoplasmic reticulum (ER) stress under nutrient scarcity. Furthermore, CAFs are less hypoxic than adjacent malignant cells in vivo, nominating them as a potential source of unsaturated lipids. CAF-conditioned medium promotes PDAC cell survival upon nutrient and oxygen deprivation, an effect reversed by delipidation. Lysophosphatidylcholines (LPCs) are particularly enriched in CAF-conditioned medium and preferentially taken up by PDAC cells, where they are converted to phosphatidylcholine (PC) to sustain membrane integrity. Blocking LPC-to-PC conversion inhibits PDAC cell survival and increases ER stress. These findings show a critical lipid "cross-feeding" mechanism that promotes PDAC cell survival, offering a potential metabolic target for treatment.
    Keywords:  CP: Cancer; CP: Metabolism; fibroblasts; hypoxia; lipids; pancreatic cancer; tumor microenvironment; unsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2024.114972
  2. Sci Adv. 2024 Nov 15. 10(46): eadp7423
    Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
    Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.
    DOI:  https://doi.org/10.1126/sciadv.adp7423
  3. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00412-1. [Epub ahead of print]
    Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
    Jivani M Gengatharan, Michal K Handzlik, Zoya Y Chih, Maureen L Ruchhoeft, Patrick Secrest, Ethan L Ashley, Courtney R Green, Martina Wallace, Philip L S M Gordts, Christian M Metallo.
      Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr-/- mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.
    Keywords:  SPTLC3; TRL remnant; VLDL; atherosclerosis; lipoprotein; monounsaturated fatty acid; myriocin; sphingolipid; sphingomyelin; trans fatty acid
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.016
  4. Nature. 2024 Nov 13.
    NK2R control of energy expenditure and feeding to treat metabolic diseases.
    Frederike Sass, Tao Ma, Jeppe H Ekberg, Melissa Kirigiti, Mario G Ureña, Lucile Dollet, Jenny M Brown, Astrid L Basse, Warren T Yacawych, Hayley B Burm, Mette K Andersen, Thomas S Nielsen, Abigail J Tomlinson, Oksana Dmytiyeva, Dan P Christensen, Lindsay Bader, Camilla T Vo, Yaxu Wang, Dylan M Rausch, Cecilie K Kristensen, María Gestal-Mato, Wietse In Het Panhuis, Kim A Sjøberg, Stace Kernodle, Jacob E Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E Jørgensen, Anders Albrechtsen, Niels Grarup, M Madan Babu, Patrick C N Rensen, Sander Kooijman, Randy J Seeley, Anna Worthmann, Joerg Heeren, Tune H Pers, Torben Hansen, Magnus B F Gustafsson, Mads Tang-Christensen, Tuomas O Kilpeläinen, Martin G Myers, Paul Kievit, Thue W Schwartz, Jakob B Hansen, Zachary Gerhart-Hines.
      The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2-4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic-euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.
    DOI:  https://doi.org/10.1038/s41586-024-08207-0
  5. Redox Biol. 2024 Oct 30. pii: S2213-2317(24)00391-4. [Epub ahead of print]78 103413
    Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization.
    Xiao Shan, Zemin Ji, Baochen Wang, Yanan Zhang, Hongyuan Dong, Weijia Jing, Yanzhao Zhou, Penghui Hu, Yan Cui, Zihan Li, Sujun Yu, Jinxue Zhou, Ting Wang, Long Shen, Yuping Liu, Qiujing Yu.
      Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.
    Keywords:  Inducible nitric oxide synthase; Macrophage polarization; Riboflavin kinase
    DOI:  https://doi.org/10.1016/j.redox.2024.103413
  6. Cell Chem Biol. 2024 Nov 07. pii: S2451-9456(24)00440-9. [Epub ahead of print]
    Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes.
    Daisuke Ogasawara, David B Konrad, Zher Yin Tan, Kimberly L Carey, Jessica Luo, Sang Joon Won, Haoxin Li, Trever R Carter, Kristen E DeMeester, Evert Njomen, Stuart L Schreiber, Ramnik J Xavier, Bruno Melillo, Benjamin F Cravatt.
      Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, remained limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these "photo-stereoprobes" interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible NanoBRET assays. Integrated phenotypic screening and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of DOS-inspired photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and facilitating the discovery and characterization of bioactive compounds in phenotypic screens.
    Keywords:  NanoBRET; autophagy; chemical proteomics; diazirine; diversity-oriented synthesis; ligands; phenotypic screening; photoreactive; probes; proteomics; stereochemistry
    DOI:  https://doi.org/10.1016/j.chembiol.2024.10.005
  7. Cancer Cell. 2024 Nov 01. pii: S1535-6108(24)00398-2. [Epub ahead of print]
    Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.
    Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P Sivaccumar, Ashwin Kumar Ramesh, Ningyan Zhang, Zhiqiang An, Shaomeng Wang, Weiping Zou.
      Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3+ cancer.
    Keywords:  NRF2; SLC13A3; SLC13A3 inhibitor; SLC7A11; T cell immunity; ferroptosis; immune checkpoint blockade; itaconate; macrophages; tumor
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.010
  8. J Leukoc Biol. 2024 Nov 12. pii: qiae240. [Epub ahead of print]
    Interleukin-10 inhibits important components of trained immunity in human monocytes.
    Rutger J Röring, Flavia Scognamiglio, Lisanne C de Jong, Laszlo A Groh, Vasiliki Matzaraki, Valerie A C M Koeken, Leo A B Joosten, Athanasios Ziogas, Mihai G Netea.
      Trained immunity induces antigen-agnostic enhancement of host defense and protection against secondary infections, but inappropriate activation can contribute to the pathophysiology of inflammatory diseases. Tight regulation of trained immunity is therefore needed to avoid pathology, but little is known about the endogenous processes that modulate it. Here, we investigated the potential of IL-10, a prototypical anti-inflammatory cytokine, to inhibit trained immunity. IL-10 induced tolerance and inhibited trained immunity in primary human monocytes at both functional and transcriptional levels. Inhibition of STAT3, a signaling route that mediates IL-10 signals, induced trained immunity. IL-10 downregulated glycolytic and oxidative metabolism in monocytes, but did not impact the metabolic effects of β-glucan-induced trained immunity. Furthermore, IL-10 prevented increased ROS production in BCG-induced training, but did not influence phagocytosis upregulation. In a cohort study of healthy volunteers vaccinated with BCG, genetic variants that influenced IL-10 or its receptor modulated BCG-induced trained immunity. Furthermore, circulating IL-10 concentrations were negatively correlated with induction of trained immunity after BCG vaccination in a sex-specific manner. In conclusion, IL-10 inhibited several, albeit not all, immunological functions amplified after induction of trained immunity. Follow-up studies should explore the precise molecular mechanism that mediate the effects of IL-10 on trained immunity. Addressing these knowledge gaps is an important step towards optimizing IL-10's potential as a therapeutic target in diseases characterized by inappropriate induction of trained immunity.
    Keywords:  IL-10; cytokines; tolerance; trained immunity
    DOI:  https://doi.org/10.1093/jleuko/qiae240
  9. Nat Commun. 2024 Nov 07. 15(1): 9652
    Preoperative methionine restriction induces perivascular adipose tissue browning and improves vein graft remodeling in male mice.
    Peter Kip, Thijs J Sluiter, Michael R MacArthur, Ming Tao, Nicky Kruit, Sarah J Mitchell, Jonathan Jung, Sander Kooijman, Josh Gorham, Jonathan G Seidman, Paul H A Quax, Julius L Decano, Masanori Aikawa, C Keith Ozaki, James R Mitchell, Margreet R de Vries.
      Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application to improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and pathologic vascular remodeling following vein graft surgery in male mice. RNA sequencing reveals that MetR enhances browning in arterial (thoracic aorta) perivascular adipose tissue (PVAT) and induces it in venous (caval vein) PVAT. Specifically, Ppara is highly upregulated in PVAT-adipocytes upon MetR. Furthermore, MetR dampens the postoperative pro-inflammatory response to surgery in PVAT-macrophages in vivo and in vitro. This study shows that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in MetR-induced browning of PVAT. Furthermore, we demonstrate the potential of short-term preoperative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.
    DOI:  https://doi.org/10.1038/s41467-024-53844-8
  10. Sci Rep. 2024 11 08. 14(1): 27182
    Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
    Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.
      Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.
    Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes
    DOI:  https://doi.org/10.1038/s41598-024-78434-y
  11. Science. 2024 Nov 15. 386(6723): eadh9215
    A glutamine metabolic switch supports erythropoiesis.
    Junhua Lyu, Zhimin Gu, Yuannyu Zhang, Hieu S Vu, Christophe Lechauve, Feng Cai, Hui Cao, Julia Keith, Valentina Brancaleoni, Francesca Granata, Irene Motta, Maria Domenica Cappellini, Lily Jun-Shen Huang, Ralph J DeBerardinis, Mitchell J Weiss, Min Ni, Jian Xu.
      Metabolic requirements vary during development, and our understanding of how metabolic activity influences cell specialization is incomplete. Here, we describe a switch from glutamine catabolism to synthesis required for erythroid cell maturation. Glutamine synthetase (GS), one of the oldest functioning genes in evolution, is activated during erythroid maturation to detoxify ammonium generated from heme biosynthesis, which is up-regulated to support hemoglobin production. Loss of GS in mouse erythroid precursors caused ammonium accumulation and oxidative stress, impairing erythroid maturation and recovery from anemia. In β-thalassemia, GS activity is inhibited by protein oxidation, leading to glutamate and ammonium accumulation, whereas enhancing GS activity alleviates the metabolic and pathological defects. Our findings identify an evolutionarily conserved metabolic adaptation that could potentially be leveraged to treat common red blood cell disorders.
    DOI:  https://doi.org/10.1126/science.adh9215
  12. Sci Adv. 2024 Nov 15. 10(46): eadp1152
    H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response.
    Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Satyajit Das, Stephanie Mills, Susana Comte-Walters, Monika Gooz, Seungho Choi, Rasesh Y Parikh, Zacharia Hedley, Silvia Vaena, Reid DeMass, Gina Scurti, Martin Romeo, Vamsi K Gangaraju, Stefano Berto, Elizabeth Hill, Lauren E Ball, Anand S Mehta, Eduardo N Maldonado, Michael I Nishimura, Besim Ogretmen, Shikhar Mehrotra.
      The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H2S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H2S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihi tumor-reactive T cells can improve tumor control upon adoptive transfer.
    DOI:  https://doi.org/10.1126/sciadv.adp1152
  13. Cancer Res. 2024 Nov 15.
    Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.
    Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech.
      Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-4027
  14. J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02474-8. [Epub ahead of print] 107972
    Acute inflammation upregulates FAHFAs in adipose tissue and in co-cultured adipocytes.
    Meric Erikci Ertunc, Srihari Konduri, Zhichen Ma, Antonio F M Pinto, Cynthia J Donaldson, Jeremiah Momper, Dionicio Siegel, Alan Saghatelian.
      Since the discovery of fatty acid hydroxy fatty acids (FAHFAs), significant progress has been made in understanding their regulation, biochemistry, and physiological activities. Here, we contribute to this understanding by revealing that inflammation induces the production of fatty acid hydroxy stearic acids (FAHSAs) and fatty acid hydroxyoctadecadienoic acids (FAHODEs) in white adipose tissue depots and in adipocytes co-cultured with macrophages. In LPS-induced co-culture systems, we confirm that adipose triglyceride lipase (ATGL) is required for inflammation-induced FAHFA generation and demonstrate that inflammation is necessary for producing hydroxy fatty acids. Chemically synthesized FAHODEs show anti-inflammatory activities in vivo, but only at supraphysiological concentrations. While endogenous FAHFAs are unlikely to be anti-inflammatory due to their low concentrations, conversion of pro-inflammatory hydroxy fatty acids into FAHFAs may modulate inflammation. We test this concept by showing the pro-inflammatory lipids-hydroxyeicosatetraenoic acids (HETEs) and leukotriene B4 (LTB4)-are converted into FAHFAs in cell culture, and that two LTB4-derived FAHFAs have are modestly anti- not pro-inflammatory. Further research is needed to establish whether these increased FAFHA levels have a role in inflammation or are simply markers of inflammation, but the discovery of significant increases in FAHFA upon acute inflammation advances our knowledge of FAHFAs.
    Keywords:  ATGL; FAHFA; HETE; HODE; LPS; LTB4; adipose tissue; inflammation; lipid
    DOI:  https://doi.org/10.1016/j.jbc.2024.107972
  15. Nat Immunol. 2024 Nov 08.
    Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.
    Ronal M Peralta, Bingxian Xie, Konstantinos Lontos, Hector Nieves-Rosado, Kellie Spahr, Supriya Joshi, B Rhodes Ford, Kevin Quann, Andrew T Frisch, Victoria Dean, Mary Philbin, Anthony R Cillo, Sebastian Gingras, Amanda C Poholek, Lawrence P Kane, Dayana B Rivadeneira, Greg M Delgoffe.
      CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.
    DOI:  https://doi.org/10.1038/s41590-024-01999-3
  16. Cancer Res. 2024 Nov 12.
    Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer.
    Wenfeng Zeng, Ruihua Zhang, Penghan Huang, Minxia Chen, Houying Chen, Xin Zeng, Jiang Liu, Jiahui Zhang, Di Huang, Liyan Lao.
      Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment (TME) need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MBOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL-1beta+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MBOAT1 expression via IL-1beta/IL-1R1/NF-kappaB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL-8 and S100A9 to replenish the neutrophil pool in the TME. Ferroptotic neutrophils in turn fostered Fer-CD4 T cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL-1beta+ CD4+ T cells or IL-1R1+ neutrophils broke the crosstalk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1941
  17. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00868-2. [Epub ahead of print]
    PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization.
    Junya Ito, Toshitaka Nakamura, Takashi Toyama, Deng Chen, Carsten Berndt, Gereon Poschmann, André Santos Dias Mourão, Sebastian Doll, Mirai Suzuki, Weijia Zhang, Jiashuo Zheng, Dietrich Trümbach, Naoya Yamada, Koya Ono, Masana Yazaki, Yasutaka Kawai, Mieko Arisawa, Yusuke Ohsaki, Hitoshi Shirakawa, Adam Wahida, Bettina Proneth, Yoshiro Saito, Kiyotaka Nakagawa, Eikan Mishima, Marcus Conrad.
      Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, the contribution of other phospholipid peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a contribution of alternative PLOOH peroxidases. By scrutinizing potential candidates, we found that although overexpression of peroxiredoxin 6 (PRDX6), a thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed to prevent ferroptosis, its genetic loss sensitizes cancer cells to ferroptosis. Mechanistically, we uncover that PRDX6, beyond its known peroxidase activity, acts as a selenium-acceptor protein, facilitating intracellular selenium utilization and efficient selenium incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated by reduced GPX4 expression in Prdx6-deficient mouse brains and increased sensitivity to ferroptosis in PRDX6-deficient tumor xenografts in mice. Our study highlights PRDX6 as a critical player in directing cellular selenium utilization and dictating ferroptosis sensitivity.
    Keywords:  GPX4; LC-MS/MS; brain; cell death; cysteine; lipid peroxidation; selenite; selenocysteine; selenoproteins; tumor
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.028
  18. Cancer Cell. 2024 Oct 30. pii: S1535-6108(24)00399-4. [Epub ahead of print]
    Itaconate promotes an unexpected tumor immune escape mechanism.
    Lara Haase, Christian Frezza.
      Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.011
  19. Elife. 2024 Nov 11. pii: RP96962. [Epub ahead of print]13
    Functional identification of soluble uric acid as an endogenous inhibitor of CD38.
    Shijie Wen, Hiroshi Arakawa, Shigeru Yokoyama, Yoshiyuki Shirasaka, Haruhiro Higashida, Ikumi Tamai.
      Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.
    Keywords:  CD38; MSU crystal; gout; hyperuricemia; hypouricemia; immunology; inflammation; metabolism; mouse; nicotinamide adenine dinucleotide; uric acid; uricase
    DOI:  https://doi.org/10.7554/eLife.96962
  20. JCI Insight. 2024 Nov 08. pii: e187849. [Epub ahead of print]9(21):
    Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
    Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.
      
    DOI:  https://doi.org/10.1172/jci.insight.187849
  21. Hepatology. 2024 Nov 07.
    Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via extracellular vesicles.
    Tsai-Ling Liao, Der-Yuan Chen, Shie-Liang Hsieh, Ying-Ying Yang, Yi-Ming Chen, Kuo-Tung Tang, Chung-Hsin Chang, Sheng-Shun Yang.
       BACKGROUND AIMS: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear.
    APPROACH RESULTS: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet-bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis.
    CONCLUSIONS: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.
    DOI:  https://doi.org/10.1097/HEP.0000000000001149
  22. FASEB Bioadv. 2024 Nov;6(11): 526-538
    Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.
    Akari Nishida, Ryuji Ohue-Kitano, Yuki Masujima, Hazuki Nonaka, Miki Igarashi, Takako Ikeda, Ikuo Kimura.
      Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long-chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high-energy content and lipotoxicity. In contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from in vitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles in vivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84-deficient mice. Although Gpr84-deficient mice were lean and had increased endogenous MCFAs under high-fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice. Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP-1 levels in wild-type mice; however, these effects were partially attenuated in Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes.
    Keywords:  GPR84; decanoates; fatty acids; high‐fat diet; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1096/fba.2024-00075
  23. Nat Cell Biol. 2024 Nov 13.
    Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ.
    Christos Kiourtis, Maria Terradas-Terradas, Lucy M Gee, Stephanie May, Anastasia Georgakopoulou, Amy L Collins, Eoin D O'Sullivan, David P Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H Reed, Lee A Borthwick, Colin Nixon, William Clark, Peter S Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K Najumudeen, Gareth J Inman, Andrew Campbell, Simon T Barry, Alberto Quaglia, Christopher M Morris, Fiona E N LeBeau, Owen J Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G Bird.
      Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01543-3
  24. FASEB J. 2024 Nov 15. 38(21): e70155
    Hemin promotes platelet activation and plasma membrane disintegration regulated by the subtilisin-like proprotein convertase furin.
    David Schaale, Zoi Laspa, Aylin Balmes, Manuel Sigle, Valerie Dicenta-Baunach, Ravi Hochuli, Xiaoqing Fu, Kristian Serafimov, Tatsiana Castor, Tobias Harm, Karin Anne Lydia Müller, Anne-Katrin Rohlfing, Stefan Laufer, Tilman E Schäffer, Michael Lämmerhofer, Meinrad Gawaz.
      Platelet activation plays a critical role in thrombosis and hemostasis. Several pathophysiological situations lead to hemolysis, resulting in the liberation of free ferric iron-containing hemin. Hemin has been shown to activate platelets and induce thrombo-inflammation. Classical antiplatelet therapy failed to prevent hemin-induced platelet activation. Thus, the aim of the present study was to characterize the mechanism of hemin-induced platelet death (ferroptosis). We evaluated the in vitro effect of hemin on platelet activation, signaling, oxylipins, and plasma membrane destruction using light transmission aggregometry, ex vivo thrombus formation, multiparametric flow cytometry, micro-UHPLC mass spectrometry for oxylipin profiling, and scanning ion conductance microscopy (SICM). We found that hemin induces platelet cell death indicated by increased ROS levels, phosphatidyl serine (PS) exposure, and loss of mitochondrial membrane potential (ΔΨm). Further, hemin causes lipid peroxidation and generation of distinct oxylipins, which strongly affects plasma membrane integrity leading to generation of platelet-derived microvesicles. Interestingly, hemin-dependent platelet death (ferroptosis) is specifically regulated by the subtilisin-like proprotein convertase furin. In summary, platelet undergo a non-apoptotic cell death mediated by furin. Inhibition of furin may offer a therapeutic strategy to control hemin-induced thrombosis and thrombo-inflammation at a site of hemolysis.
    Keywords:  ferroptosis; furin; hemin; microvesicle; platelets
    DOI:  https://doi.org/10.1096/fj.202400863RR
  25. Cell Rep Methods. 2024 Nov 06. pii: S2667-2375(24)00294-7. [Epub ahead of print] 100904
    Elucidating the spatiotemporal dynamics of glucose metabolism with genetically encoded fluorescent biosensors.
    Xie Li, Xueyi Wen, Weitao Tang, Chengnuo Wang, Yaqiong Chen, Yi Yang, Zhuo Zhang, Yuzheng Zhao.
      Glucose metabolism has been well understood for many years, but some intriguing questions remain regarding the subcellular distribution, transport, and functions of glycolytic metabolites. To address these issues, a living cell metabolic monitoring technology with high spatiotemporal resolution is needed. Genetically encoded fluorescent sensors can achieve specific, sensitive, and spatiotemporally resolved metabolic monitoring in living cells and in vivo, and dozens of glucose metabolite sensors have been developed recently. Here, we highlight the importance of tracking specific intermediate metabolites of glycolysis and glycolytic flux measurements, monitoring the spatiotemporal dynamics, and quantifying metabolite abundance. We then describe the working principles of fluorescent protein sensors and summarize the existing biosensors and their application in understanding glucose metabolism. Finally, we analyze the remaining challenges in developing high-quality biosensors and the huge potential of biosensor-based metabolic monitoring at multiple spatiotemporal scales.
    Keywords:  CP: Metabolism
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100904
  26. Nat Commun. 2024 Nov 11. 15(1): 9756
    Nonvesicular lipid transfer drives myelin growth in the central nervous system.
    Jianping Wu, Georg Kislinger, Jerome Duschek, Ayşe Damla Durmaz, Benedikt Wefers, Ruoqing Feng, Karsten Nalbach, Wolfgang Wurst, Christian Behrends, Martina Schifferer, Mikael Simons.
      Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into and making contact with the innermost myelin layer where growth occurs. We explore the possibility of transfer of lipids from the ER to myelin, and find that the glycolipid transfer protein (GLTP), implicated in nonvesicular lipid transport, is highly enriched in the growing myelin sheath. Mice with a specific knockout of Gltp in oligodendrocytes exhibit ER pathology, hypomyelination and a decrease in myelin glycolipid content. In summary, our results demonstrate a role for nonvesicular lipid transport in CNS myelin growth, revealing a cellular pathway in developmental myelination.
    DOI:  https://doi.org/10.1038/s41467-024-53511-y
  27. Acta Pharm Sin B. 2024 Oct;14(10): 4461-4477
    Spatial metabolomics highlights metabolic reprogramming in acute myeloid leukemia mice through creatine pathway.
    Yucheng Bao, Jing Qiao, Wenjie Gong, Ruihong Zhang, Yanting Zhou, Yinyin Xie, Yuan Xie, Jiuming He, Tong Yin.
      Acute myeloid leukemia (AML) is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming. Here, we applied spatial metabolomics to achieve high-throughput, in situ identification of metabolites within the liver metastases of AML mice. Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics. This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle, coupled with an upregulation of the creatine metabolism. The upregulation of creatine synthetases Gatm and Gamt, as well as the creatine transporter Slc6a8, resulted in a marked accumulation of creatine within tumor foci. This process further enhances oxidative phosphorylation and glycolysis of leukemia cells, thereby boosting ATP production to foster proliferation and infiltration. Importantly, we discovered that inhibiting Slc6a8 can counter these detrimental effects, offering a new strategy for treating AML by targeting metabolic pathways.
    Keywords:  Acute myeloid leukemia; Creatine; Glycolysis; Metabolic reprogramming; Metastasis; Oxidative phosphorylation; Slc6a8; Spatial metabolomics
    DOI:  https://doi.org/10.1016/j.apsb.2024.07.004
  28. Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01325-1. [Epub ahead of print]43(11): 114974
    A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling.
    Bodie Curren, Tufael Ahmed, Ridwan B Rashid, Ismail Sebina, Md Al Amin Sikder, Daniel R Howard, Mariah Alorro, Md Ashik Ullah, Alec Bissell, Muhammed Mahfuzur Rahman, Michael A Pearen, Grant A Ramm, Antiopi Varelias, Stefan Rose-John, Kelli P A MacDonald, Robert Hoelzle, Páraic Ó Cuív, Kirsten M Spann, Paul G Dennis, Simon Phipps.
      A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver. Inhibition of IL-6 trans-signaling using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.
    Keywords:  ALRI; CP: Immunology; CP: Metabolism; IL-6 trans-signaling; RSV; asthma; bronchiolitis; liver; low grade systemic inflammation; maternal diet; microbiome; neutrophils
    DOI:  https://doi.org/10.1016/j.celrep.2024.114974
  29. Front Mol Biosci. 2024 ;11 1480617
    The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases.
    Aihong Peng, Junqin Li, Jianxiao Xing, Yuanjun Yao, Xuping Niu, Kaiming Zhang.
      Nicotinamide phosphoribosyl transferase (NAMPT) is a rate-limiting enzyme in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway, and plays a vital role in the regulation of cell metabolic activity, reprogramming, aging and apoptosis. NAMPT synthesizes nicotinamide mononucleotide (NMN) through enzymatic action, which is a key protein involved in host defense mechanism and plays an important role in metabolic homeostasis and cell survival. NAMPT is involved in NAD metabolism and maintains intracellular NAD levels. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs), the members are capable of sensing cellular NAD+ levels. NAMPT-NAD and SIRT constitute a powerful anti-stress defense system. In this paper, the structure, biological function and correlation with diseases of NAMPT are introduced, aiming to provide new ideas for the targeted therapy of related diseases.
    Keywords:  NAD metabolism; NAMPT; SIRTs; biological function; diseases
    DOI:  https://doi.org/10.3389/fmolb.2024.1480617
  30. Cell. 2024 Nov 07. pii: S0092-8674(24)01214-5. [Epub ahead of print]
    A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.
    Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.
      β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.
    Keywords:  BHB; enzyme; ketone; metabolite; metabolomics; obesity
    DOI:  https://doi.org/10.1016/j.cell.2024.10.032
  31. Nat Cell Biol. 2024 Nov 07.
    Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.
    Tian Zhang, Weixin Fu, Haosong Zhang, Jianlong Li, Beizi Xing, Yuping Cai, Mengmeng Zhang, Xuheng Liu, Chunting Qi, Lihui Qian, Xinbo Hu, Hua Zhu, Shuailong Yang, Min Zhang, Jianping Liu, Ganquan Li, Yang Li, Rong Xiang, Zhengqiang Qi, Junhao Hu, Ying Li, Chengyu Zou, Qin Wang, Xia Jin, Rui Pang, Peiying Li, Junli Liu, Yaoyang Zhang, Zhaoyin Wang, Zheng-Jiang Zhu, Bing Shan, Junying Yuan.
      It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41556-024-01540-6
  32. Am J Respir Cell Mol Biol. 2024 Nov 12.
    Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.
    Christina Sul, Caitlin V Lewis, Janelle Posey, Mariah Jordan, Daniel Colon Hidalgo, Timothy Porfilio, Hanan Elajaili, Genevieve McCormack, Samuel Burciaga, Cassidy Delaney, Eva S Nozik.
      Acute respiratory distress syndrome (ARDS) is a serious illness accounting for 10% of ICU admissions and high mortality of 31-45% with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of ARDS. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD), are protected against Staphylococcus aureus (S. aureus) pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue binding affinity and elevated alveolar and plasma EC-SOD levels, though the redox-regulated mechanisms responsible for protection against S. aureus are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against S. aureus pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared to WT mice with S. aureus pneumonia, platelet activation, formation of platelet-neutrophil aggregates (PNAs), and influx of neutrophils and PNAs into the lung are decreased in the infected R213G mice. Furthermore, pre-treatment with a MnTE-2-PyP SOD mimetic protects against S. aureus-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of S. aureus-induced acute lung injury.
    Keywords:  Platelet activation; Redox; S. aureus pneumonia; pulmonary neutrophilia
    DOI:  https://doi.org/10.1165/rcmb.2024-0292OC
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒27 at 14:58.