bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–04–09
thirty papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells.
  2. Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
  3. Nicotinamide-N-methyltransferase regulates lipid metabolism via SAM and 1-methylnicotinamide in the AML12 hepatocyte cell line.
  4. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
  5. Duodenal macrophages control dietary iron absorption via local degradation of transferrin.
  6. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  7. NAD+ repletion with niacin counteracts cancer cachexia.
  8. MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming.
  9. Reciprocal intra- and extra-cellular polarity enables deep mechanosensing through layered matrices.
  10. Triglyceride cycling enables modification of stored fatty acids.
  11. Macrophage function in adipose tissue homeostasis and metabolic inflammation.
  12. Deficiency of neutrophil high-mobility group box protein-1, in liver transplant recipients, exacerbates early allograft injury in mice.
  13. Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.
  14. A Plasmodium falciparum lysophospholipase regulates host fatty acid flux via parasite lipid storage to enable controlled asexual schizogony.
  15. MACROPHAGE-DERIVED OSTEOPONTIN (SPP1) PROTECTS FROM NON-ALCOHOLIC STEATOHEPATITIS.
  16. Matrix stiffness regulates tumor cell intravasation through expression and ESRP1-mediated alternative splicing of MENA.
  17. Neurons require glucose uptake and glycolysis in vivo.
  18. Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.
  19. Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation.
  20. Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
  21. Tumor microenvironment mimicking 3D models unveil the multifaceted effects of SMAC mimetics.
  22. Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases.
  23. Quantification of Serum Metabolites in Early Colorectal Adenomas Using Isobaric Labeling Mass Spectrometry.
  24. Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway.
  25. Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow.
  26. Crotonylation of GAPDH regulates human embryonic stem cell endodermal lineage differentiation and metabolic switch.
  27. Altered acylcarnitine metabolism and inflexible mitochondrial fuel utilization characterize the loss of neonatal myocardial regeneration capacity.
  28. TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques.
  29. Spatial probabilistic mapping of metabolite ensembles in mass spectrometry imaging.
  30. Innate-like T lymphocytes in chronic liver disease.
  1. Nat Metab. 2023 Apr 06.
    The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells.
    Deepti Talwar, Colin G Miller, Justus Grossmann, Lukasz Szyrwiel, Torsten Schwecke, Vadim Demichev, Ana-Matea Mikecin Drazic, Anand Mayakonda, Pavlo Lutsik, Carmen Veith, Michael D Milsom, Karin Müller-Decker, Michael Mülleder, Markus Ralser, Tobias P Dick.
      Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity. Specifically, we find that anchorage-independent growth of cells and spheroids is limited by an elevation of endogenous peroxide levels and is largely dependent on a functional GAPDH redox switch. Likewise, tumour growth in vivo is limited by peroxide stress and suppressed when the GAPDH redox switch is disabled in tumour cells. The induction of additional intratumoural oxidative stress by chemo- or radiotherapy synergized with the deactivation of the GAPDH redox switch. Mice lacking the GAPDH redox switch exhibit altered fatty acid metabolism in kidney and heart, apparently in compensation for the lack of the redox switch. Together, our findings demonstrate the physiological and pathophysiological relevance of oxidative GAPDH inactivation in mammals.
    DOI:  https://doi.org/10.1038/s42255-023-00781-3
  2. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00085-2. [Epub ahead of print]35(4): 711-721.e4
    Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
    Qishan Chen, Hu Li, He Tian, Sin Man Lam, Yilie Liao, Ziyin Zhang, Manyuan Dong, Shaoru Chen, Yuxiao Yao, Jiemiao Meng, Yong Zhang, Lemin Zheng, Zhuo-Xian Meng, Weiping Han, Guanghou Shui, Dahai Zhu, Suneng Fu.
      Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.
    Keywords:  dietary fluxomics; elementary metabolite units; inter-organ metabolite flow; multi-organ EMU modeling
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.007
  3. J Biochem. 2023 Apr 04. pii: mvad028. [Epub ahead of print]
    Nicotinamide-N-methyltransferase regulates lipid metabolism via SAM and 1-methylnicotinamide in the AML12 hepatocyte cell line.
    Mayuko Yoda, Rin Mizuno, Yoshihiro Izumi, Masatomo Takahashi, Takeshi Bamba, Shinpei Kawaoka.
      Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knock down Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total neutral lipids upon Nnmt RNAi. Treating Nnmt RNAi AML12 cells with cycloleucine, an inhibitor of SAM biogenesis suppresses SAM accumulation and rescues the decrease of neutral lipids. MNAM also shows activity to elevate neutral lipids. These results suggest that NNMT contributes to lipid metabolism by maintaining proper SAM and MNAM homeostasis. This study provides an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism.
    DOI:  https://doi.org/10.1093/jb/mvad028
  4. Nat Metab. 2023 Apr 03.
    Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
    Alanna C Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S A Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser.
      Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
    DOI:  https://doi.org/10.1038/s42255-023-00771-5
  5. Blood. 2023 Apr 05. pii: blood.2022016632. [Epub ahead of print]
    Duodenal macrophages control dietary iron absorption via local degradation of transferrin.
    Nyamdelger Sukhbaatar, Maria Schöller, Stephanie Deborah Fritsch, Monika Linke, Stefanie Horer, Manuela Träger, Mario Mazic, Stephan Forisch, Karine Gonzales, Jan Pascal Kahler, Carina Binder, Caroline Lassnig, Birgit Strobl, Mathias Mueller, Barbara Scheiber-Mojdehkar, Claudia Gundacker, Stefanie Dabsch, Renate Kain, Markus Hengstschläger, Steven Verhelst, Günter Weiss, Igor Theurl, Thomas Weichhart.
      Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin, the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, we found that these mice possessed various defects in iron metabolism including defective steady state erythropoiesis and a reduced saturation of transferrin with iron. This iron-deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of transferrin, whereas depletion of macrophages in mice increased transferrin levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored transferrin levels in the Tsc2-deficient mice as well as transferrin saturation. Physiologically, transferrin levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling transferrin availability in the lamina propria villi.
    DOI:  https://doi.org/10.1182/blood.2022016632
  6. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  7. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  8. Nat Commun. 2023 Apr 01. 14(1): 1830
    MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming.
    Morgane Mabire, Pushpa Hegde, Adel Hammoutene, Jinghong Wan, Charles Caër, Rola Al Sayegh, Mathilde Cadoux, Manon Allaire, Emmanuel Weiss, Tristan Thibault-Sogorb, Olivier Lantz, Michèle Goodhardt, Valérie Paradis, Pierre de la Grange, Hélène Gilgenkrantz, Sophie Lotersztajn.
      Recent data have shown that liver fibrosis can regress even at later stages of cirrhosis and shifting the immune response from pro-inflammatory towards a resolutive profile is considered as a promising option. The immune regulatory networks that govern the shift of the inflammatory phenotype and thus potential reversal of liver fibrosis are lesser known. Here we show that in precision-cut human liver slices obtained from patients with end-stage fibrosis and in mouse models, inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches, limits fibrosis progression and even regresses fibrosis, following chronic toxic- or non-alcoholic steatohepatitis (NASH)-induced liver injury. Mechanistic studies, combining RNA sequencing, in vivo functional studies (performed in male mice) and co-culture experiments indicate that disruption of the MAIT cell-monocyte/macrophage interaction results in resolution of fibrosis both by increasing the frequency of restorative Ly6Clo at the expenses of pro-fibrogenic Ly6Chi monocyte-derived macrophages and promoting an autophagic phenotype in both subsets. Thus, our data show that MAIT cell activation and the consequential phenotype shift of liver macrophages are important pathogenic features of liver fibrosis and could be targeted by anti-fibrogenic therapy.
    DOI:  https://doi.org/10.1038/s41467-023-37453-5
  9. Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00373-X. [Epub ahead of print]42(4): 112362
    Reciprocal intra- and extra-cellular polarity enables deep mechanosensing through layered matrices.
    Christopher Walter, Jairaj Mathur, Amit Pathak.
      Adherent cells migrate on layered tissue interfaces to drive morphogenesis, wound healing, and tumor invasion. Although stiffer surfaces are known to enhance cell migration, it remains unclear whether cells sense basal stiff environments buried under softer, fibrous matrix. Using layered collagen-polyacrylamide gel systems, we unveil a migration phenotype driven by cell-matrix polarity. Here, cancer (but not normal) cells with stiff base matrix generate stable protrusions, faster migration, and greater collagen deformation because of "depth mechanosensing" through the top collagen layer. Cancer cell protrusions with front-rear polarity produce polarized collagen stiffening and deformations. Disruption of either extracellular or intracellular polarity via collagen crosslinking, laser ablation, or Arp2/3 inhibition independently abrogates depth-mechanosensitive migration of cancer cells. Our experimental findings, validated by lattice-based energy minimization modeling, present a cell migration mechanism whereby polarized cellular protrusions and contractility are reciprocated by mechanical extracellular polarity, culminating in a cell-type-dependent ability to mechanosense through matrix layers.
    Keywords:  CP: Cell biology; atomic force microscopy; cell migration; cell polarity; collagen; depth sensing; extracellular matrix polarity; laser ablation; layered matrix; mechanobiology; mechanosensing
    DOI:  https://doi.org/10.1016/j.celrep.2023.112362
  10. Nat Metab. 2023 Apr 03.
    Triglyceride cycling enables modification of stored fatty acids.
    Klaus Wunderling, Jelena Zurkovic, Fabian Zink, Lars Kuerschner, Christoph Thiele.
      Triglyceride cycling is the process of continuous degradation and re-synthesis of triglyceride in cellular stores. We show in 3T3-L1 adipocytes that triglycerides are subject to rapid turnover and re-arrangement of fatty acids with an estimated half-life of 2-4 h. We develop a tracing technology that can simultaneously and quantitatively follow the metabolism of multiple fatty acids to study the triglyceride futile substrate cycle directly and with molecular species resolution. Our approach is based on alkyne fatty acid tracers and mass spectrometry. The triglyceride cycling is connected to modification of released fatty acids by elongation and desaturation. Through cycling and modification, saturated fatty acids are slowly converted to monounsaturated fatty acids, and linoleic acid to arachidonic acid. We conclude that triglyceride cycling renders stored fatty acids accessible for metabolic alteration. The overall process facilitates cellular adjustments to the stored fatty acid pool to meet changing needs of the cell.
    DOI:  https://doi.org/10.1038/s42255-023-00769-z
  11. Nat Immunol. 2023 Apr 03.
    Macrophage function in adipose tissue homeostasis and metabolic inflammation.
    Triantafyllos Chavakis, Vasileia Ismini Alexaki, Anthony W Ferrante.
      Obesity-related metabolic organ inflammation contributes to cardiometabolic disorders. In obese individuals, changes in lipid fluxes and storage elicit immune responses in the adipose tissue (AT), including expansion of immune cell populations and qualitative changes in the function of these cells. Although traditional models of metabolic inflammation posit that these immune responses disturb metabolic organ function, studies now suggest that immune cells, especially AT macrophages (ATMs), also have important adaptive functions in lipid homeostasis in states in which the metabolic function of adipocytes is taxed. Adverse consequences of AT metabolic inflammation might result from failure to maintain local lipid homeostasis and long-term effects on immune cells beyond the AT. Here we review the complex function of ATMs in AT homeostasis and metabolic inflammation. Additionally, we hypothesize that trained immunity, which involves long-term functional adaptations of myeloid cells and their bone marrow progenitors, can provide a model by which metabolic perturbations trigger chronic systemic inflammation.
    DOI:  https://doi.org/10.1038/s41590-023-01479-0
  12. Hepatology. 2023 Apr 06.
    Deficiency of neutrophil high-mobility group box protein-1, in liver transplant recipients, exacerbates early allograft injury in mice.
    Zhuolun Song, Hui Han, Xiaodong Ge, Sukanta Das, Romain Desert, Dipti Athavale, Wei Chen, Sai Santosh Babu Komakula, Daniel Lantvit, Natalia Nieto.
       BACKGROUND AIMS: Early allograft dysfunction (EAD) is a severe event, leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury, remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients, protects from post-LT EAD.
    APPROACH RESULTS: We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients, exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts, did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells, increased reactive oxygen species (ROS) and inflammation in liver grafts, and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). Upon LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver, and enhanced production of ROS and pro-inflammatory cytokines, when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody (Ab), attenuated graft injury in recipients with myeloid cell Hmgb1 ablation.
    CONCLUSIONS: Neutrophil HMGB1 from recipients is central to regulate their activation, limiting production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.
    DOI:  https://doi.org/10.1097/HEP.0000000000000346
  13. Cell Metab. 2023 Mar 29. pii: S1550-4131(23)00088-8. [Epub ahead of print]
    Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.
    Qin Zeng, Shuyi Wang, Mengyuan Li, Shuang Wang, Chaohuan Guo, Xinyuan Ruan, Ryu Watanabe, Yimei Lai, Yuefang Huang, Xiaoyu Yin, Chuanzhao Zhang, Binfeng Chen, Niansheng Yang, Hui Zhang.
      Autoreactive B cell responses are essential for the development of systemic lupus erythematosus (SLE). Fibroblastic reticular cells (FRCs) are known to construct lymphoid compartments and regulate immune functions. Here, we identify spleen FRC-derived acetylcholine (ACh) as a key factor that controls autoreactive B cell responses in SLE. In SLE, CD36-mediated lipid uptake leads to enhanced mitochondrial oxidative phosphorylation in B cells. Accordingly, the inhibition of fatty acid oxidation results in reduced autoreactive B cell responses and ameliorated diseases in lupus mice. Ablation of CD36 in B cells impairs lipid uptake and differentiation of autoreactive B cells during autoimmune induction. Mechanistically, spleen FRC-derived ACh promotes lipid influx and generation of autoreactive B cells through CD36. Together, our data uncover a novel function of spleen FRCs in lipid metabolism and B cell differentiation, placing spleen FRC-derived ACh in a key position in promoting autoreactive B cells in SLE.
    Keywords:  CD36; acetylcholine; autoreactive B cell responses; choline acetyltransferase; fibroblastic reticular cells; lipid metabolism; mitochondrial respiration; spleen; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.010
  14. Cell Rep. 2023 Mar 30. pii: S2211-1247(23)00262-0. [Epub ahead of print] 112251
    A Plasmodium falciparum lysophospholipase regulates host fatty acid flux via parasite lipid storage to enable controlled asexual schizogony.
    Pradeep Kumar Sheokand, Yoshiki Yamaryo-Botté, Monika Narwal, Christophe-Sébastien Arnold, Vandana Thakur, Md Muzahidul Islam, Mudassir M Banday, Mohd Asad, Cyrille Y Botté, Asif Mohmmed.
      Phospholipid metabolism is crucial for membrane biogenesis and homeostasis of Plasmodium falciparum. To generate such phospholipids, the parasite extensively scavenges, recycles, and reassembles host lipids. P. falciparum possesses an unusually large number of lysophospholipases, whose roles and importance remain to be elucidated. Here, we functionally characterize one P. falciparum lysophospholipase, PfLPL3, to reveal its key role in parasite propagation during asexual blood stages. PfLPL3 displays a dynamic localization throughout asexual stages, mainly localizing in the host-parasite interface. Inducible knockdown of PfLPL3 disrupts parasite development from trophozoites to schizont, inducing a drastic reduction in merozoite progenies. Detailed lipidomic analyses show that PfLPL3 generates fatty acids from scavenged host lipids to generate neutral lipids. These are then timely mobilized to allow schizogony and merozoite formation. We then identify inhibitors of PfLPL3 from Medicine for Malaria Venture (MMV) with potent antimalarial activity, which could also serve as pertinent chemical tools to study parasite lipid synthesis.
    Keywords:  CP: parasitology; Plasmodium falciparum; TAG/triglycerides; drugs; lipid flux; lipid metabolism; lipidomics; lysophospholipase; malaria; membrane biogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112251
  15. Gastroenterology. 2023 Apr 05. pii: S0016-5085(23)00581-4. [Epub ahead of print]
    MACROPHAGE-DERIVED OSTEOPONTIN (SPP1) PROTECTS FROM NON-ALCOHOLIC STEATOHEPATITIS.
    Hui Han, Xiaodong Ge, Sai Santosh Babu Komakula, Romain Desert, Sukanta Das, Zhuolun Song, Wei Chen, Dipti Athavale, Harriet Gaskell, Daniel Lantvit, Grace Guzman, Natalia Nieto.
       BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether macrophage-derived OPN affects NASH progression is unknown.
    METHODS: We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose and cholesterol diet mimicking the Western diet, to induce NASH.
    RESULTS: This study demonstrated that MFs expressing high SPP1 are enriched in patients and mice with NAFLD, and show metabolic but not inflammatory properties. Spp1KI Mye or Spp1KI LvMF conferred protection, whereas OpnΔMye worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1KI Mye mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1KI Mye also protected through sex-specific extrahepatic mechanisms.
    CONCLUSION: MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for NAFLD patients.
    Keywords:  arginase 2; inflammation; steatosis
    DOI:  https://doi.org/10.1053/j.gastro.2023.03.228
  16. Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00349-2. [Epub ahead of print]42(4): 112338
    Matrix stiffness regulates tumor cell intravasation through expression and ESRP1-mediated alternative splicing of MENA.
    Wenjun Wang, Paul V Taufalele, Martial Millet, Kevin Homsy, Kyra Smart, Emily D Berestesky, Curtis T Schunk, Matthew M Rowe, Francois Bordeleau, Cynthia A Reinhart-King.
      During intravasation, cancer cells cross the endothelial barrier and enter the circulation. Extracellular matrix stiffening has been correlated with tumor metastatic potential; however, little is known about the effects of matrix stiffness on intravasation. Here, we utilize in vitro systems, a mouse model, specimens from patients with breast cancer, and RNA expression profiles from The Cancer Genome Atlas Program (TCGA) to investigate the molecular mechanism by which matrix stiffening promotes tumor cell intravasation. Our data show that heightened matrix stiffness increases MENA expression, which promotes contractility and intravasation through focal adhesion kinase activity. Further, matrix stiffening decreases epithelial splicing regulatory protein 1 (ESRP1) expression, which triggers alternative splicing of MENA, decreases the expression of MENA11a, and enhances contractility and intravasation. Altogether, our data indicate that matrix stiffness regulates tumor cell intravasation through enhanced expression and ESRP1-mediated alternative splicing of MENA, providing a mechanism by which matrix stiffness regulates tumor cell intravasation.
    Keywords:  CP: Cancer; ECM stiffness; ENAH; RNA splicing; epithelial splicing regulatory protein 1; trans-endothelial migration
    DOI:  https://doi.org/10.1016/j.celrep.2023.112338
  17. Cell Rep. 2023 Apr 06. pii: S2211-1247(23)00346-7. [Epub ahead of print]42(4): 112335
    Neurons require glucose uptake and glycolysis in vivo.
    Huihui Li, Caroline Guglielmetti, Yoshitaka J Sei, Misha Zilberter, Lydia M Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L Dayton, Martin Kampmann, Yadong Huang, Jeffrey C Rathmell, Matthew Vander Heiden, Myriam M Chaumeil, Ken Nakamura.
      Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.
    Keywords:  CP: Neuroscience; bioenergetics; brain energy; galactose metabolism; glucose transporter; glycolysis; hyperpolarized magnetic resonance spectroscopic imaging; metabolomics; neuronal glucose metabolism; pyruvate kinase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112335
  18. Cell Rep. 2023 Mar 29. pii: S2211-1247(23)00326-1. [Epub ahead of print] 112315
    Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.
    Kazuhiro Morishita, Kengo Watanabe, Isao Naguro, Hidenori Ichijo.
      Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na+) influx regulates the condensate liquidity under hyperosmotic stress. ASK3 condensates have higher fluidity at the high intracellular Na+ concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na+ influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na+ widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ, and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na+ contribute to the cellular stress response via liquidity maintenance of biomolecular condensates.
    Keywords:  CP: Molecular biology; biomolecular condensate; liquidity; osmotic stress; phase separation; polyQ; protein aggregation; sodium ion
    DOI:  https://doi.org/10.1016/j.celrep.2023.112315
  19. Sci Immunol. 2023 Apr 14. 8(82): eadd8945
    Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation.
    Thomas Fabre, Alexander M S Barron, Stephen M Christensen, Shoh Asano, Kathryn Bound, Matthew P Lech, Marc H Wadsworth, Xiao Chen, Chang Wang, Ju Wang, James McMahon, Franklin Schlerman, Alexis White, Kellie M Kravarik, Andrew J Fisher, Lee A Borthwick, Kevin M Hart, Neil C Henderson, Thomas A Wynn, Ken Dower.
      Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, and CD63. In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1-induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.
    DOI:  https://doi.org/10.1126/sciimmunol.add8945
  20. Haematologica. 2023 Apr 06.
    Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
    Cristiana O'Brien, Tianyi Ling, Jacob M Berman, Rachel Culp-Hill, Julie A Reisz, Vincent Rondeau, Soheil Jahangiri, Jonathan St-Germain, Vinitha Macwan, Audrey Astori, Andy Zeng, Jun Young Hong, Meng Li, Min Yang, Sadhan Jana, Fabia Gamboni, Emily Tsao, Weiyi Liu, John E Dick, Hening Lin, Ari Melnick, Anastasia Tikhonova, Andrea Arruda, Mark D Minden, Brian Raught, Angelo D'Alessandro, Courtney L Jones.
      Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease initiating leukemia stem cells (LSCs). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSCs. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSCs. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSCs but is not essential for normal human hematopoietic stem and progenitor cell (HSPC) function. To elucidate the molecular mechanisms by which SIRT3 is essential in LSCs we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support oxidative phosphorylation and ATP production in human LSCs. Further, we discovered two approaches to further sensitize LSCs to SIRT3 inhibition. First, we found that LSCs tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSCs to YC8-02 and potentiates LSC cell death. Second, SIRT3 inhibition sensitizes LSCs to BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.
    DOI:  https://doi.org/10.3324/haematol.2022.281894
  21. iScience. 2023 Apr 21. 26(4): 106381
    Tumor microenvironment mimicking 3D models unveil the multifaceted effects of SMAC mimetics.
    Catarina Pinto, Ksenija Slavic-Obradovic, Daniela Fürweger, Barbara Thaler, Abdallah Souabni, Sebastian Carotta, Martin Aichinger, Ulrich Reiser, Maria Antonietta Impagnatiello, Iñigo Tirapu.
      Small molecule IAP antagonists - SMAC mimetics (SM) - are being developed as an anticancer therapy. SM therapy was demonstrated not only to sensitize tumor cells to TNFα-mediated cell death but also to exert immunostimulatory properties. Their good safety and tolerability profile, plus promising preclinical data, warrants further investigation into their various effects within the tumor microenvironment. Using in vitro models of human tumor cells and fibroblast spheroids co-cultured with primary immune cells, we investigated the effects of SM on immune cell activation. SM treatment induces the maturation of human PBMC- and patient-derived dendritic cells (DC), and modulates cancer-associated fibroblasts towards an immune interacting phenotype. Finally, SM-induced tumor necroptosis further enhances DC activation, leading also to higher T-cell activation and infiltration into the tumor site. These results highlight the relevance of using heterotypic in vitro models to investigate the effects of targeted therapies on different components of the tumor microenvironment.
    Keywords:  Biological sciences; Cancer; Cancer systems biology; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106381
  22. Elife. 2023 04 03. pii: e83217. [Epub ahead of print]12
    Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases.
    Eleftheria Koropouli, Qiang Wang, Rebeca Mejías, Randal Hand, Tao Wang, David D Ginty, Alex L Kolodkin.
      Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp1)/PlexA4, respectively. We find that Nrp2 and Nrp1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp2 cysteines is required for its proper subcellular localization, cell surface clustering, and also for Sema3F/Nrp2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo. Moreover, we show that the palmitoyl acyltransferase ZDHHC15 is required for Nrp2 palmitoylation and Sema3F/Nrp2-dependent dendritic spine pruning, but it is dispensable for Nrp1 palmitoylation and Sema3A/Nrp1-dependent basal dendritic elaboration. Therefore, palmitoyl acyltransferase-substrate specificity is essential for establishing compartmentalized neuronal structure and functional responses to extrinsic guidance cues.
    Keywords:  Sema3F; cortical neurons; mouse; neuropilin-2; neuropilins; neuroscience; palmitoyl acyltransferases; palmitoylation
    DOI:  https://doi.org/10.7554/eLife.83217
  23. J Proteome Res. 2023 Apr 04.
    Quantification of Serum Metabolites in Early Colorectal Adenomas Using Isobaric Labeling Mass Spectrometry.
    Yuan Liu, Hua Zhang, William F Dove, Zicong Wang, Zhijun Zhu, Perry J Pickhardt, Mark Reichelderfer, Lingjun Li.
      A major challenge in reducing the death rate of colorectal cancer is to screen patients using low-invasive testing. A blood test shows a high compliance rate with reduced invasiveness. In this work, a multiplex isobaric tag labeling strategy coupled with mass spectrometry is adopted to relatively quantify primary and secondary amine-containing metabolites in serum for the discovery of metabolite level changes of colorectal cancer. Serum samples from patients at different risk statuses and colorectal cancer growth statuses are studied. Metabolite identification is based on accurate mass matching and/or retention time of labeled metabolite standards. We quantify 40 metabolites across all the serum samples, including 18 metabolites validated with standards. We find significantly decreased levels of threonine and asparagine in the patients with growing adenomas or high-risk adenomas (p < 0.05). Glutamine levels decrease in patients with adenomas of unknown growth status or high-risk adenomas. In contrast, arginine levels are elevated in patients with low-risk adenoma. Receiver operating characteristic analysis shows high sensitivity and specificity of these metabolites for detecting growing adenomas. Based on these results, we conclude that a few metabolites identified here might contribute to distinguishing colorectal patients with growing adenomas from normal individuals and patients with unknown growth status of adenomas.
    Keywords:  colorectal cancer; isobaric tag; mass spectrometry; metabolomics; multiplex labeling; serum biomarker
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00006
  24. Hum Mol Genet. 2023 Apr 03. pii: ddad052. [Epub ahead of print]
    Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway.
    Lu Xu, Lile Wang, Rongna Yang, Tianxiang Li, Xiaoli Zhu.
       BACKGROUND: There is increasing evidence that exosome-mediated transmission of microRNA (miRNAs) helps to connect tumor-associated macrophages and cancer cells, including lung adenocarcinoma (LUAD) cells.
    PURPOSE: To identify the role of miR-3153 in LUAD progression and M2 macrophage polarization and explore its regulatory mechanism.
    METHODS: The relevant molecular mechanisms were analyzed and validated through mechanistic assays. In vitro functional assays followed by in vivo experiments were implemented to evaluate the role of exosomes in mediating M2 macrophage polarization and LUAD progression.
    RESULTS: LUAD cells transmitted miR-3153 through exosomes. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) promoted miR-3153 biosynthesis and exosomal sorting. Exosomal miR-3153 targeted zinc finger protein 91 (ZFP91) to suppress the ubiquitination and degradation of misshapen-like kinase 1 (MINK1), thereby activating the c-Jun N-terminal kinase (JNK) signaling pathway and inducing M2 macrophage polarization. M2 macrophage polarization induced by LUAD cell-derived exosomes promoted the malignant process of LUAD cells.
    CONCLUSION: Transmission of exosomal miR-3153 by LUAD cells activates the JNK signaling pathway and induces M2 macrophage polarization, thus promoting the progression of LUAD.
    DOI:  https://doi.org/10.1093/hmg/ddad052
  25. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00083-9. [Epub ahead of print]35(4): 667-684.e6
    Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow.
    Xiaonan Liu, Yiru Gu, Surendra Kumar, Sahran Amin, Qiaoyue Guo, Jiekang Wang, Ching-Lien Fang, Xu Cao, Mei Wan.
      The chronic use of glucocorticoids decreases bone mass and quality and increases bone-marrow adiposity, but the underlying mechanisms remain unclear. Here, we show that bone-marrow adipocyte (BMAd) lineage cells in adult mice undergo rapid cellular senescence upon glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype, which spreads senescence in bone and bone marrow. Mechanistically, glucocorticoids increase the synthesis of oxylipins, such as 15d-PGJ2, for peroxisome proliferator-activated receptor gamma (PPARγ) activation. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce the secondary spread of senescent cells and bone-loss phenotypes, whereas transplanting BMAds harboring a p16INK4a deletion did not show such effects. Thus, glucocorticoid treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of glucocorticoid-induced bone deterioration.
    Keywords:  INK-family proteins; PPARγ; bone marrow adipocytes; bone marrow adiposity; cellular senescence; glucocorticoids; osteoporosis; oxylipins; prostaglandins; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.005
  26. Stem Cell Res Ther. 2023 Apr 03. 14(1): 63
    Crotonylation of GAPDH regulates human embryonic stem cell endodermal lineage differentiation and metabolic switch.
    Jingran Zhang, Guang Shi, Junjie Pang, Xing Zhu, Qingcai Feng, Jie Na, Wenbin Ma, Dan Liu, Zhou Songyang.
       BACKGROUND: Post-translational modifications of proteins are crucial to the regulation of their activity and function. As a newly discovered acylation modification, crotonylation of non-histone proteins remains largely unexplored, particularly in human embryonic stem cells (hESCs).
    METHODS: We investigated the role of crotonylation in hESC differentiation by introduce crotonate into the culture medium of GFP tagged LTR7 primed H9 cell and extended pluripotent stem cell lines. RNA-seq assay was used to determine the hESC transcriptional features. Through morphological changes, qPCR of pluripotent and germ layer-specific gene markers and flow cytometry analysis, we determined that the induced crotonylation resulted in hESC differentiating into the endodermal lineage. We performed targeted metabolomic analysis and seahorse metabolic measurement to investigate the metabolism features after crotonate induction. Then high-resolution tandem mass spectrometry (LC-MS/MS) revealed the target proteins in hESCs. In addition, the role of crotonylated glycolytic enzymes (GAPDH and ENOA) was evaluated by in vitro crotonylation and enzymatic activity assays. Finally, we used knocked-down hESCs by shRNA, wild GAPDH and GAPDH mutants to explore potential role of GAPDH crotonylation in regulating human embryonic stem cell differentiation and metabolic switch.
    RESULT: We found that induced crotonylation in hESCs resulted in hESCs of different pluripotency states differentiating into the endodermal lineage. Increased protein crotonylation in hESCs was accompanied by transcriptomic shifts and decreased glycolysis. Large-scale crotonylation profiling of non-histone proteins revealed that metabolic enzymes were major targets of inducible crotonylation in hESCs. We further discovered GAPDH as a key glycolytic enzyme regulated by crotonylation during endodermal differentiation from hESCs.
    CONCLUSIONS: Crotonylation of GAPDH decreased its enzymatic activity thereby leading to reduced glycolysis during endodermal differentiation from hESCs.
    Keywords:  Crotonylation; Embryonic stem cell; Endodermal differentiation; GAPDH; Metabolic switch
    DOI:  https://doi.org/10.1186/s13287-023-03290-y
  27. Exp Mol Med. 2023 Apr 03.
    Altered acylcarnitine metabolism and inflexible mitochondrial fuel utilization characterize the loss of neonatal myocardial regeneration capacity.
    E Kankuri, P Finckenberg, J Leinonen, M Tarkia, S Björk, J Purhonen, J Kallijärvi, M Kankainen, R Soliymani, M Lalowski, E Mervaala.
      Myocardial regeneration capacity declines during the first week after birth, and this decline is linked to adaptation to oxidative metabolism. Utilizing this regenerative window, we characterized the metabolic changes in myocardial injury in 1-day-old regeneration-competent and 7-day-old regeneration-compromised mice. The mice were either sham-operated or received left anterior descending coronary artery ligation to induce myocardial infarction (MI) and acute ischemic heart failure. Myocardial samples were collected 21 days after operations for metabolomic, transcriptomic and proteomic analyses. Phenotypic characterizations were carried out using echocardiography, histology and mitochondrial structural and functional assessments. In both groups, MI induced an early decline in cardiac function that persisted in the regeneration-compromised mice over time. By integrating the findings from metabolomic, transcriptomic and proteomic examinations, we linked regeneration failure to the accumulation of long-chain acylcarnitines and insufficient metabolic capacity for fatty acid beta-oxidation. Decreased expression of the redox-sensitive mitochondrial Slc25a20 carnitine-acylcarnitine translocase together with a decreased reduced:oxidized glutathione ratio in the myocardium in the regeneration-compromised mice pointed to a defect in the redox-sensitive acylcarnitine transport to the mitochondrial matrix. Rather than a forced shift from the preferred adult myocardial oxidative fuel source, our results suggest the facilitation of mitochondrial fatty acid transport and improvement of the beta-oxidation pathway as a means to overcome the metabolic barrier for repair and regeneration in adult mammals after MI and heart failure.
    DOI:  https://doi.org/10.1038/s12276-023-00967-5
  28. Nat Commun. 2023 Apr 06. 14(1): 1914
    TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques.
    Amit A Upadhyay, Elise G Viox, Timothy N Hoang, Arun K Boddapati, Maria Pino, Michelle Y-H Lee, Jacqueline Corry, Zachary Strongin, David A Cowan, Elizabeth N Beagle, Tristan R Horton, Sydney Hamilton, Hadj Aoued, Justin L Harper, Christopher T Edwards, Kevin Nguyen, Kathryn L Pellegrini, Gregory K Tharp, Anne Piantadosi, Rebecca D Levit, Rama R Amara, Simon M Barratt-Boyes, Susan P Ribeiro, Rafick P Sekaly, Thomas H Vanderford, Raymond F Schinazi, Mirko Paiardini, Steven E Bosinger.
      The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.
    DOI:  https://doi.org/10.1038/s41467-023-37425-9
  29. Nat Commun. 2023 Apr 01. 14(1): 1823
    Spatial probabilistic mapping of metabolite ensembles in mass spectrometry imaging.
    Denis Abu Sammour, James L Cairns, Tobias Boskamp, Christian Marsching, Tobias Kessler, Carina Ramallo Guevara, Verena Panitz, Ahmed Sadik, Jonas Cordes, Stefan Schmidt, Shad A Mohammed, Miriam F Rittel, Mirco Friedrich, Michael Platten, Ivo Wolf, Andreas von Deimling, Christiane A Opitz, Wolfgang Wick, Carsten Hopf.
      Mass spectrometry imaging vows to enable simultaneous spatially resolved investigation of hundreds of metabolites in tissues, but it primarily relies on traditional ion images for non-data-driven metabolite visualization and analysis. The rendering and interpretation of ion images neither considers nonlinearities in the resolving power of mass spectrometers nor does it yet evaluate the statistical significance of differential spatial metabolite abundance. Here, we outline the computational framework moleculaR ( https://github.com/CeMOS-Mannheim/moleculaR ) that is expected to improve signal reliability by data-dependent Gaussian-weighting of ion intensities and that introduces probabilistic molecular mapping of statistically significant nonrandom patterns of relative spatial abundance of metabolites-of-interest in tissue. moleculaR also enables cross-tissue statistical comparisons and collective molecular projections of entire biomolecular ensembles followed by their spatial statistical significance evaluation on a single tissue plane. It thereby fosters the spatially resolved investigation of ion milieus, lipid remodeling pathways, or complex scores like the adenylate energy charge within the same image.
    DOI:  https://doi.org/10.1038/s41467-023-37394-z
  30. Front Immunol. 2023 ;14 1114605
    Innate-like T lymphocytes in chronic liver disease.
    Maria Papanastasatou, Mihalis Verykokakis.
      In addition to its metabolic activities, it is now clear that the liver hosts a number of diverse immune cell types that control tissue homeostasis. Foremost among these are innate-like T lymphocytes, including natural killer T (NKT) and mucosal-associated innate T (MAIT) cells, which are a population of specialized T cells with innate characteristics that express semi-invariant T cell receptors with non-peptide antigen specificity. As primary liver residents, innate-like T cells have been associated with immune tolerance in the liver, but also with a number of hepatic diseases. Here, we focus on the biology of NKT and MAIT cells and how they operate during the course of chronic inflammatory diseases that eventually lead to hepatocellular carcinoma.
    Keywords:  HCC; NAFLD; NASH; chronic inflammation; innate-like T cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1114605
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