bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–07–21
23 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
  2. Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice.
  3. Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma.
  4. Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
  5. Adipose glutaminolysis resurfaces in metabolic disease.
  6. Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
  7. Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
  8. Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts.
  9. Regulation of and challenges in targeting NAD+ metabolism.
  10. Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
  11. IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer.
  12. Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.
  13. CX3CR1+ macrophages interact with hepatic stellate cells to promote hepatocellular carcinoma through CD8+ T cell suppression.
  14. Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.
  15. An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake.
  16. Mitochondrial perturbations in low-protein-diet-fed mice are associated with altered neutrophil development and effector functions.
  17. Analysis and Quantification of the Mitochondrial-ER Lipidome.
  18. A metabolic atlas of blood cells in young and aged mice identifies uridine as a metabolite to rejuvenate aged hematopoietic stem cells.
  19. Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule.
  20. Small-molecule probe for IBD risk variant GPR65 I231L alters cytokine signaling networks through positive allosteric modulation.
  21. H2S as a metabolic saboteur.
  22. T cell dysfunction and therapeutic intervention in cancer.
  23. Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression.
  1. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00845-3. [Epub ahead of print]43(8): 114516
    Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation.
    Stuart Leishman, Najd M Aljadeed, Liyunhe Qian, Shamshad Cockcroft, Jacques Behmoaras, Paras K Anand.
      Despite its significance, the role of lipid metabolism in NLRP3 inflammasome remains elusive. Here, we reveal a critical role for fatty acid synthase (FASN) in NLRP3 inflammasome activation. We demonstrate that pharmacological or genetic depletion of FASN dampens NLRP3 activation in primary mouse and human macrophages and in mice. This disruption in NLRP3 activation is contingent upon FASN activity. Accordingly, abolishing cellular palmitoylation, a post-translational modification in which the FASN product palmitate is reversibly conjugated to cysteine residues of target proteins, blunts inflammasome signaling. Correspondingly, an acyl-biotin exchange assay corroborated NLRP3 palmitoylation. Mechanistically, Toll-like receptor (TLR) ligation introduces palmitoylation at NLRP3 Cys898, permitting NLRP3 translocation to dispersed trans-Golgi network (dTGN) vesicles, the site of inflammasome assembly, upon NLRP3 activation. Accordingly, the NLRP3 Cys898 mutant exhibits reduced palmitoylation, limited translocation to the dTGN compartment, and diminished inflammasome activation. These results underscore mechanistic insights through which lipid metabolism licenses NLRP3 inflammasome assembly and activation.
    Keywords:  CP: Immunology; CP: Metabolism; FASN; NLRP3; SREBP1; immunometabolism; inflammasome; lipid biosynthesis; lipid metabolism; palmitoylation; pyroptosis; trans Golgi network
    DOI:  https://doi.org/10.1016/j.celrep.2024.114516
  2. Nat Metab. 2024 Jul 19.
    Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice.
    Qingqing Qi, Huijie Zhang, Zheyu Jin, Changchun Wang, Mengyu Xia, Bandy Chen, Bomin Lv, Ludmila Peres Diaz, Xue Li, Ru Feng, Mengdi Qiu, Yang Li, David Meseguer, Xiaojiao Zheng, Wei Wang, Wei Song, He Huang, Hao Wu, Lei Chen, Marc Schneeberger, Xiaofei Yu.
      Dysbiosis of the gut microbiota has been implicated in the pathogenesis of metabolic syndrome (MetS) and may impair host metabolism through harmful metabolites. Here, we show that Desulfovibrio, an intestinal symbiont enriched in patients with MetS, suppresses the production of the gut hormone glucagon-like peptide 1 (GLP-1) through the production of hydrogen sulfide (H2S) in male mice. Desulfovibrio-derived H2S is found to inhibit mitochondrial respiration and induce the unfolded protein response in intestinal L cells, thereby hindering GLP-1 secretion and gene expression. Remarkably, blocking Desulfovibrio and H2S with an over-the-counter drug, bismuth subsalicylate, improves GLP-1 production and ameliorates diet-induced metabolic disorder in male mice. Together, our study uncovers that Desulfovibrio-derived H2S compromises GLP-1 production, shedding light on the gut-relayed mechanisms by which harmful microbiota-derived metabolites impair host metabolism in MetS and suggesting new possibilities for treating MetS.
    DOI:  https://doi.org/10.1038/s42255-024-01068-x
  3. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00826-X. [Epub ahead of print]43(8): 114497
    Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma.
    Kruthi Suvarna, Panneerselvam Jayabal, Xiuye Ma, Hu Wang, Yidong Chen, Susan T Weintraub, Xianlin Han, Peter J Houghton, Yuzuru Shiio.
      Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.
    Keywords:  CP: Cancer; CP: Metabolism; Ewing sarcoma; GPR64; RIF1; SMPD1; SPOP; ceramide; proteomics; secretome
    DOI:  https://doi.org/10.1016/j.celrep.2024.114497
  4. Sci Immunol. 2024 Jul 19. 9(97): eadl1903
    Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
    Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N J McKenzie, Mark S Cragg, Matthew Hoare, David R Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y F Halim.
      Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adl1903
  5. Nat Metab. 2024 Jul 15.
    Adipose glutaminolysis resurfaces in metabolic disease.
    John A Haley, David A Guertin.
      
    DOI:  https://doi.org/10.1038/s42255-024-01084-x
  6. Nat Commun. 2024 Jul 18. 15(1): 6067
    Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
    Marvin Hering, Alaa Madi, Roger Sandhoff, Sicong Ma, Jingxia Wu, Alessa Mieg, Karsten Richter, Kerstin Mohr, Nora Knabe, Diana Stichling, Gernot Poschet, Felix Bestvater, Larissa Frank, Jochen Utikal, Viktor Umansky, Guoliang Cui.
      After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.
    DOI:  https://doi.org/10.1038/s41467-024-50341-w
  7. Nat Commun. 2024 Jul 16. 15(1): 5980
    Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
    Nikita Sushentsev, Gregory Hamm, Lucy Flint, Daniel Birtles, Aleksandr Zakirov, Jack Richings, Stephanie Ling, Jennifer Y Tan, Mary A McLean, Vinay Ayyappan, Ines Horvat Menih, Cara Brodie, Jodi L Miller, Ian G Mills, Vincent J Gnanapragasam, Anne Y Warren, Simon T Barry, Richard J A Goodwin, Tristan Barrett, Ferdia A Gallagher.
      Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-024-50362-5
  8. Immunity. 2024 Jul 09. pii: S1074-7613(24)00318-2. [Epub ahead of print]
    Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts.
    Yoshitaka Taketomi, Takayoshi Higashi, Kuniyuki Kano, Yoshimi Miki, Chika Mochizuki, Shota Toyoshima, Yoshimichi Okayama, Yasumasa Nishito, Susumu Nakae, Satoshi Tanaka, Suzumi M Tokuoka, Yoshiya Oda, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Noriyuki Akahoshi, Satoshi Ishii, Jerold Chun, Junken Aoki, Makoto Murakami.
      Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
    Keywords:  anaphylaxis; fibroblast; lipid mediator; lysophosphatidic acid; mast cell; phospholipase A(2); prostaglandin
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.012
  9. Nat Rev Mol Cell Biol. 2024 Jul 18.
    Regulation of and challenges in targeting NAD+ metabolism.
    Marie E Migaud, Mathias Ziegler, Joseph A Baur.
      Nicotinamide adenine dinucleotide, in its oxidized (NAD+) and reduced (NADH) forms, is a reduction-oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD+ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD+ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD+ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD+ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD+ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD+ and NADH, and non-canonical NAD+ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD+, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD+ levels in humans.
    DOI:  https://doi.org/10.1038/s41580-024-00752-w
  10. Cell Death Dis. 2024 Jul 18. 15(7): 513
    Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
    Charles L Bidgood, Lisa K Philp, Anja Rockstroh, Melanie Lehman, Colleen C Nelson, Martin C Sadowski, Jennifer H Gunter.
      Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.
    DOI:  https://doi.org/10.1038/s41419-024-06893-2
  11. Nat Commun. 2024 Jul 19. 15(1): 6079
    IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer.
    Lies van Baarle, Veronica De Simone, Linda Schneider, Sneha Santhosh, Saeed Abdurahiman, Francesca Biscu, Reiner Schneider, Lisa Zanoletti, Renata Siqueira de Mello, Sara Verbandt, Zedong Hu, Michelle Stakenborg, Bo-Jun Ke, Nathalie Stakenborg, Raquel Salvador Laureano, Balbina García-Reyes, Jonas Henn, Marieta Toma, Maxime Vanmechelen, Guy Boeckxstaens, Frederik De Smet, Abhishek D Garg, Sales Ibiza, Sabine Tejpar, Sven Wehner, Gianluca Matteoli.
      Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-50438-2
  12. Immunity. 2024 Jul 06. pii: S1074-7613(24)00316-9. [Epub ahead of print]
    Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood.
    Olaf Perdijk, Alana Butler, Matthew Macowan, Roxanne Chatzis, Edyta Bulanda, Rhiannon D Grant, Nicola L Harris, Tomasz P Wypych, Benjamin J Marsland.
      Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.
    Keywords:  airway epithelial cells; allergy; antibiotics; early life; gut-lung axis; indole-3-propionic acid; metabolites; microbiota; redox balance; window of opportunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.010
  13. Hepatology. 2024 Jul 19.
    CX3CR1+ macrophages interact with hepatic stellate cells to promote hepatocellular carcinoma through CD8+ T cell suppression.
    Jong-Min Jeong, Sung Eun Choi, Young-Ri Shim, Hee-Hoon Kim, Young-Sun Lee, Keungmo Yang, Kyurae Kim, Min Jeong Kim, Katherine Po Sin Chung, Seok-Hwan Kim, Jin-Seok Byun, Hyuk Soo Eun, Won-Il Jeong.
       BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area.
    APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR‒ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development.
    CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.
    DOI:  https://doi.org/10.1097/HEP.0000000000001021
  14. Nat Metab. 2024 Jul 15.
    Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.
    Simon Lecoutre, Salwan Maqdasy, David Rizo-Roca, Gianluca Renzi, Ivan Vlassakev, Lynn M Alaeddine, Romane Higos, Jutta Jalkanen, Jiawei Zhong, Danae S Zareifi, Scott Frendo-Cumbo, Lucas Massier, Ondrej Hodek, Marta Juvany, Thomas Moritz, Thais de Castro Barbosa, Muhmmad Omar-Hmeadi, Marta López-Yus, Fatiha Merabtene, Jimon Boniface Abatan, Geneviève Marcelin, Elie-Julien El Hachem, Christine Rouault, Martin O Bergo, Paul Petrus, Juleen R Zierath, Karine Clément, Anna Krook, Niklas Mejhert, Mikael Rydén.
      Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.
    DOI:  https://doi.org/10.1038/s42255-024-01083-y
  15. Cell Rep. 2024 Jul 13. pii: S2211-1247(24)00838-6. [Epub ahead of print]43(7): 114509
    An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake.
    Mia Apuschkin, Hayley B Burm, Jan H Schmidt, Louise J Skov, Rita C Andersen, Carl-Fredrik Bowin, Jonatan F Støier, Kathrine L Jensen, Leonie P Posselt, Oksana Dmytriyeva, Andreas T Sørensen, Kristoffer L Egerod, Birgitte Holst, Mattias Rickhag, Thue W Schwartz, Ulrik Gether.
      Midbrain dopaminergic neurons (DANs) are subject to extensive metabotropic regulation, but the repertoire of G protein-coupled receptors (GPCRs) present in these neurons has not been mapped. Here, we isolate DANs from Dat-eGFP mice to generate a GPCR atlas by unbiased qPCR array expression analysis of 377 GPCRs. Combined with data mining of scRNA-seq databases, we identify multiple receptors in DAN subpopulations with 38 of these receptors representing the majority of transcripts. We identify 41 receptors expressed in midbrain DANs but not in non-DAN midbrain cells, including the free fatty acid receptor 4 (FFAR4). Functional expression of FFAR4 is validated by ex vivo Ca2+ imaging, and in vivo experiments support that FFAR4 negatively regulates food and water intake and bodyweight. In addition to providing a critical framework for understanding metabotropic DAN regulation, our data suggest fatty acid sensing by FFAR4 as a mechanism linking high-energy intake to the dopamine-reward pathway.
    Keywords:  CP: Metabolism; CP: Neuroscience; Dat-eGFP mice; FFAR4; G protein-coupled receptors; array analysis; dopamine; fatty acids; fluorescence-activated cell sorting; gpr120; heterogeneity; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114509
  16. Cell Rep. 2024 Jul 18. pii: S2211-1247(24)00822-2. [Epub ahead of print]43(8): 114493
    Mitochondrial perturbations in low-protein-diet-fed mice are associated with altered neutrophil development and effector functions.
    Mehakpreet K Thind, Emiliano Miraglia, Catriona Ling, Meraj A Khan, Aida Glembocki, Celine Bourdon, YueYing ChenMi, Nades Palaniyar, Michael Glogauer, Robert H J Bandsma, Amber Farooqui.
      Severe malnutrition is associated with infections, namely lower respiratory tract infections (LRTIs), diarrhea, and sepsis, and underlies the high risk of morbidity and mortality in children under 5 years of age. Dysregulations in neutrophil responses in the acute phase of infection are speculated to underlie these severe adverse outcomes; however, very little is known about their biology in this context. Here, in a lipopolysaccharide-challenged low-protein diet (LPD) mouse model, as a model of malnutrition, we show that protein deficiency disrupts neutrophil mitochondrial dynamics and ATP generation to obstruct the neutrophil differentiation cascade. This promotes the accumulation of atypical immature neutrophils that are incapable of optimal antimicrobial response and, in turn, exacerbate systemic pathogen spread and the permeability of the alveolocapillary membrane with the resultant lung damage. Thus, this perturbed response may contribute to higher mortality risk in malnutrition. We also offer a nutritional therapeutic strategy, nicotinamide, to boost neutrophil-mediated immunity in LPD-fed mice.
    Keywords:  CP: Immunology; CP: Microbiology; cellular metabolism; development and functions; immunometabolism; low-protein diet; malnutrition; neutrophils
    DOI:  https://doi.org/10.1016/j.celrep.2024.114493
  17. Bio Protoc. 2024 Jul 05. 14(13): e5028
    Analysis and Quantification of the Mitochondrial-ER Lipidome.
    Alexis R Diaz-Vegas, Anthony S Don, James G Burchfield.
      Mitochondria are vital organelles essential for cellular functions, but their lipid composition and response to stressors are not fully understood. Recent advancements in lipidomics reveal insights into lipid functions, especially their roles in metabolic perturbations and diseases. Previous methods have focused on the protein composition of mitochondria and mitochondrial-associated membranes. The advantage of our technique is that it combines organelle isolation with targeted lipidomics, offering new insights into the composition and dynamics of these organelles in pathological conditions. We developed a mitochondria isolation protocol for L6 myotubes, enabling lipidomics analysis of specific organelles without interference from other cellular compartments. This approach offers a unique opportunity to dissect lipid dynamics within mitochondria and their associated ER compartments under cellular stress. Key features • Analysis and quantification of lipids in mitochondria-ER fraction through liquid chromatography-tandem mass spectrometry-based lipidomics (LC-MS/MS lipidomics). • LC-MS/MS lipidomics provide precise and unbiased information on the lipid composition in in vitro systems. • LC-MS/MS lipidomics facilitates the identification of lipid signatures in mammalian cells.
    Keywords:  Cardiolipin; Ceramides; Endoplasmic reticulum; Lipidomics; Mitochondria; Subcellular fractionation
    DOI:  https://doi.org/10.21769/BioProtoc.5028
  18. Nat Aging. 2024 Jul 17.
    A metabolic atlas of blood cells in young and aged mice identifies uridine as a metabolite to rejuvenate aged hematopoietic stem cells.
    Xiangjun Zeng, Ce Shi, Yingli Han, Kejia Hu, Xiaoqing Li, Cong Wei, Lijuan Ding, Jiazhen Cui, Simao Huang, Yulin Xu, Meng Zhang, Wei Shan, Qian Luo, Jian Yu, Zhongzheng Zheng, Xia Li, Pengxu Qian, He Huang.
      Aging of hematopoietic stem cells (HSCs) is accompanied by impaired self-renewal ability, myeloid skewing, immunodeficiencies and increased susceptibility to malignancies. Although previous studies highlighted the pivotal roles of individual metabolites in hematopoiesis, comprehensive and high-resolution metabolomic profiles of different hematopoietic cells across ages are still lacking. In this study, we created a metabolome atlas of different blood cells across ages in mice. We reveal here that purine, pyrimidine and retinol metabolism are enriched in young hematopoietic stem and progenitor cells (HSPCs), whereas glutamate and sphingolipid metabolism are concentrated in aged HSPCs. Through metabolic screening, we identified uridine as a potential regulator to rejuvenate aged HSPCs. Mechanistically, uridine treatment upregulates the FoxO signaling pathway and enhances self-renewal while suppressing inflammation in aged HSCs. Finally, we constructed an open-source platform for public easy access and metabolomic analysis in blood cells. Collectively, we provide a resource for metabolic studies in hematopoiesis that can contribute to future anti-aging metabolite screening.
    DOI:  https://doi.org/10.1038/s43587-024-00669-1
  19. Nat Commun. 2024 Jul 17. 15(1): 6002
    Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule.
    Chuan Qin, Leonie G Graf, Kilian Striska, Markus Janetzky, Norman Geist, Robin Specht, Sabrina Schulze, Gottfried J Palm, Britta Girbardt, Babett Dörre, Leona Berndt, Stefan Kemnitz, Mark Doerr, Uwe T Bornscheuer, Mihaela Delcea, Michael Lammers.
      The AMP-forming acetyl-CoA synthetase is regulated by lysine acetylation both in bacteria and eukaryotes. However, the underlying mechanism is poorly understood. The Bacillus subtilis acetyltransferase AcuA and the AMP-forming acetyl-CoA synthetase AcsA form an AcuA•AcsA complex, dissociating upon lysine acetylation of AcsA by AcuA. Crystal structures of AcsA from Chloroflexota bacterium in the apo form and in complex with acetyl-adenosine-5'-monophosphate (acetyl-AMP) support the flexible C-terminal domain adopting different conformations. AlphaFold2 predictions suggest binding of AcuA stabilizes AcsA in an undescribed conformation. We show the AcuA•AcsA complex dissociates upon acetyl-coenzyme A (acetyl-CoA) dependent acetylation of AcsA by AcuA. We discover an intrinsic phosphotransacetylase activity enabling AcuA•AcsA generating acetyl-CoA from acetyl-phosphate (AcP) and coenzyme A (CoA) used by AcuA to acetylate and inactivate AcsA. Here, we provide mechanistic insights into the regulation of AMP-forming acetyl-CoA synthetases by lysine acetylation and discover an intrinsic phosphotransacetylase allowing modulation of its activity based on AcP and CoA levels.
    DOI:  https://doi.org/10.1038/s41467-024-49952-0
  20. Sci Adv. 2024 Jul 19. 10(29): eadn2339
    Small-molecule probe for IBD risk variant GPR65 I231L alters cytokine signaling networks through positive allosteric modulation.
    Ilona Neale, Clark Reddy, Zher Yin Tan, Bihua Li, Partha P Nag, Joshua Park, Jihye Park, Kimberly L Carey, Daniel B Graham, Ramnik J Xavier.
      The proton-sensing heterotrimeric guanine nucleotide-binding protein-coupled receptor GPR65 is expressed in immune cells and regulates tissue homeostasis in response to decreased extracellular pH, which occurs in the context of inflammation and tumorigenesis. Genome-wide association studies linked GPR65 to several autoimmune and inflammatory diseases such as multiple sclerosis and inflammatory bowel disease (IBD). The loss-of-function GPR65 I231L IBD risk variant alters cellular metabolism, impairs protective tissue functions, and increases proinflammatory cytokine production. Hypothesizing that a small molecule designed to potentiate GPR65 at subphysiological pH could decrease inflammatory responses, we found positive allosteric modulators of GPR65 that engage and activate both human and mouse orthologs of the receptor. We observed that the chemical probe BRD5075 alters cytokine and chemokine programs in dendritic cells, establishing that immune signaling can be modulated by targeting GPR65. Our investigation offers improved chemical probes to further interrogate the biology of human GPR65 and its clinically relevant genetic variants.
    DOI:  https://doi.org/10.1126/sciadv.adn2339
  21. Nat Metab. 2024 Jul 19.
    H2S as a metabolic saboteur.
    Naisi Zhao, Guojun Wu, Liping Zhao.
      
    DOI:  https://doi.org/10.1038/s42255-024-01086-9
  22. Nat Immunol. 2024 Jul 18.
    T cell dysfunction and therapeutic intervention in cancer.
    Caitlin C Zebley, Dietmar Zehn, Stephen Gottshalk, Hongbo Chi.
      Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.
    DOI:  https://doi.org/10.1038/s41590-024-01896-9
  23. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00846-5. [Epub ahead of print]43(8): 114517
    Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression.
    Tomofumi Yamamoto, Jun Nakayama, Fumihiko Urabe, Kagenori Ito, Nao Nishida-Aoki, Masami Kitagawa, Akira Yokoi, Masahiko Kuroda, Yutaka Hattori, Yusuke Yamamoto, Takahiro Ochiya.
      Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment to benefit their own growth and survive in the patient's body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA library to reveal the universal mechanisms of EV secretion from cancer cells. Here, we identified miR-891b and its direct target gene, phosphoserine aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of EV secretion from cancer cells. Interestingly, aberrant PSAT1 expression also regulated cancer metastasis via EV secretion. Our data link the PSAT1-controlled EV secretion mechanism and cancer metastasis and show the potential of this mechanism as a therapeutic target in multiple types of cancer.
    Keywords:  CP: Neuroscience; exosomes; extracellular vesicles; metabolism; metastasis; serine
    DOI:  https://doi.org/10.1016/j.celrep.2024.114517
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