bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–11–26
nineteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Cardiac macrophage metabolism in health and disease.
  2. A century of the Warburg effect.
  3. Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
  4. Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.
  5. Adhesion GPCRs in glioblastoma revisited.
  6. Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity.
  7. Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders.
  8. Hypoxia-activated prodrug and anti-angiogenic therapy cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.
  9. A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.
  10. On-tissue dataset-dependent MALDI-TIMS-MS2 bioimaging.
  11. Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses.
  12. Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain.
  13. Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
  14. Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury.
  15. Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.
  16. Human V-ATPase a-subunit isoforms bind specifically to distinct phosphoinositide phospholipids.
  17. A metabolic axis of immune intractability.
  18. Metaflammation in obesity and its therapeutic targeting.
  19. Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
  1. Trends Endocrinol Metab. 2023 Nov 21. pii: S1043-2760(23)00237-0. [Epub ahead of print]
    Cardiac macrophage metabolism in health and disease.
    Benjamin J Kopecky, Kory J Lavine.
      Cardiac macrophages are essential mediators of cardiac development, tissue homeostasis, and response to injury. Cell-intrinsic shifts in metabolism and availability of metabolites regulate macrophage function. The human and mouse heart contain a heterogeneous compilation of cardiac macrophages that are derived from at least two distinct lineages. In this review, we detail the unique functional roles and metabolic profiles of tissue-resident and monocyte-derived cardiac macrophages during embryonic development and adult tissue homeostasis and in response to pathologic and physiologic stressors. We discuss the metabolic preferences of each macrophage lineage and how metabolism influences monocyte fate specification. Finally, we highlight the contribution of cardiac macrophages and derived metabolites on cell-cell communication, metabolic health, and disease pathogenesis.
    Keywords:  HFpEF; cardiac; exercise; infarction; macrophage; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2023.10.011
  2. Nat Metab. 2023 Nov;5(11): 1840-1843
    A century of the Warburg effect.
    Craig B Thompson, Karen H Vousden, Randall S Johnson, Willem H Koppenol, Helmut Sies, Zhimin Lu, Lydia W S Finley, Christian Frezza, Jiyeon Kim, Zeping Hu, Caroline R Bartman.
      
    DOI:  https://doi.org/10.1038/s42255-023-00927-3
  3. Nat Commun. 2023 11 18. 14(1): 7525
    Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
    Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.
      The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.
    DOI:  https://doi.org/10.1038/s41467-023-42824-z
  4. J Biol Chem. 2023 Nov 20. pii: S0021-9258(23)02513-9. [Epub ahead of print] 105485
    Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.
    Teresa W-M Fan, Jahid M M Islam, Richard M Higashi, Penghui Lin, Christine F Brainson, Andrew N Lane.
      EZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug EPZ-6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in three-dimensional (3D) tissue and cell culture systems influences this blockade in terms of growth-related metabolic functions. Here, we show that EZH2 suppression reduced growth of human lung adenocarcinoma A549 cells in two-dimensional (2D) cultures but stimulated growth in 3D culture. To understand the metabolic underpinnings, we employed [13C6]-glucose Stable Isotope-Resolved Metabolomics (SIRM) to determine the effect of EZH2 suppression on metabolic networks in 2D versus 3D A549 cultures. The Krebs cycle, neoribogenesis, γ-aminobutyrate (GAB) metabolism, and salvage synthesis of purine nucleotides were activated by EZH2 suppression in 3D spheroids but not in 2D cells, consistent with the growth effect. Using simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 inhibition of H3 trimethylation, we delineated the effects on the Krebs cycle, γ-aminobutyrate metabolism, gluconeogenesis, and purine salvage to be PRC2 dependent. Furthermore, the growth/metabolic effects differed for mouse Matrigel versus self-produced A549 extracellular matrix. Thus, our findings highlight the importance of the presence and nature of extracellular matrix in studying the function of EZH2 and its inhibitors in cancer cells for modeling the in vivo outcomes.
    Keywords:  EZH2; Stable Isotope-Resolved Metabolomics; extracellular matrix; glucose/glutamine metabolism; spheroids
    DOI:  https://doi.org/10.1016/j.jbc.2023.105485
  5. Cell Rep. 2023 Nov 22. pii: S2211-1247(23)01486-9. [Epub ahead of print]42(12): 113474
    Adhesion GPCRs in glioblastoma revisited.
    Tobias Langenhan.
      Glioblastoma is a devastating brain malignancy that has remained intractable to modern cancer treatments. Ravn-Boess et al.1 have discovered that the adhesion G protein-coupled receptor CD97/ADGRE5 contributes to glioblastogenesis and makes for an excellent molecular surface marker flagging the tumor cells.
    DOI:  https://doi.org/10.1016/j.celrep.2023.113474
  6. Nature. 2023 Nov 22.
    Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity.
    Ankit Malik, Deepika Sharma, Raúl Aguirre-Gamboa, Shaina McGrath, Sarah Zabala, Christopher Weber, Bana Jabri.
      All nucleated cells express major histocompatibility complex I and interferon-γ (IFNγ) receptor1, but an epithelial cell-specific function of IFNγ signalling or antigen presentation by means of major histocompatibility complex I has not been explored. We show here that on sensing IFNγ, colonic epithelial cells productively present pathogen and self-derived antigens to cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers extracellular ATPase expression in cognate intra-epithelial T cells, which limits the accumulation of extracellular adenosine triphosphate and consequent activation of the NLRP3 inflammasome in tissue macrophages. By contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated interleukin-1α and interleukin-1β production promotes a pathogenic transformation of CD4+ T cells into granulocyte-macrophage colony-stimulating-factor (GM-CSF)-producing T cells in vivo, which promotes colitis and colorectal cancer. Taken together, our study unravels critical checkpoints requiring IFNγ sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo.
    DOI:  https://doi.org/10.1038/s41586-023-06721-1
  7. Sci Transl Med. 2023 Nov 22. 15(723): eade8460
    Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders.
    Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue-Nan Sun, Zhuzhen Zhang, Jan-Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C Wyler, May-Yun Wang, Juli Bai, Xianlin Han, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Joel K Elmquist, Olivia Osborn, Chen Liu, Philipp E Scherer.
      Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.
    DOI:  https://doi.org/10.1126/scitranslmed.ade8460
  8. JCI Insight. 2023 Nov 21. pii: e169150. [Epub ahead of print]
    Hypoxia-activated prodrug and anti-angiogenic therapy cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.
    Arthur Liu, Seth T Gammon, Federica Pisaneschi, Akash Boda, Casey R Ager, David Piwnica-Worms, David S Hong, Michael A Curran.
      We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12DTP53+/R172HPdx1-Cre (KPC) derived model of pancreatic adenocarcinoma (PDAC) to examine the tumor response and adaptive resistance mechanisms involved in response to two established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast to prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8 T cell response. Bulk-tumor RNA sequencing, flow cytometry, and adoptive myeloid cell transfer suggested that treated tumor cells increased their capacity to recruit granulocytic myeloid derived suppressor cells (G-MDSC) through CCL9 secretion. Blockade of the CCL9-CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302 and anti-VEGFR-2 with ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization, and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
    Keywords:  Angiogenesis; Cancer immunotherapy; Hypoxia; Neutrophils; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.169150
  9. Nat Commun. 2023 Nov 23. 14(1): 7674
    A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.
    Sebastian Schmidt, Constantin Stautner, Duc Tung Vu, Alexander Heinz, Martin Regensburger, Ozge Karayel, Dietrich Trümbach, Anna Artati, Sabine Kaltenhäuser, Mohamed Zakaria Nassef, Sina Hembach, Letyfee Steinert, Beate Winner, Winkler Jürgen, Martin Jastroch, Malte D Luecken, Fabian J Theis, Gil Gregor Westmeyer, Jerzy Adamski, Matthias Mann, Karsten Hiller, Florian Giesert, Daniela M Vogt Weisenhorn, Wolfgang Wurst.
      Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.
    DOI:  https://doi.org/10.1038/s41467-023-42862-7
  10. Nat Commun. 2023 11 18. 14(1): 7495
    On-tissue dataset-dependent MALDI-TIMS-MS2 bioimaging.
    Steffen Heuckeroth, Arne Behrens, Carina Wolf, Arne Fütterer, Ilona D Nordhorn, Katharina Kronenberg, Corinna Brungs, Ansgar Korf, Henning Richter, Astrid Jeibmann, Uwe Karst, Robin Schmid.
      Trapped ion mobility spectrometry (TIMS) adds an additional separation dimension to mass spectrometry (MS) imaging, however, the lack of fragmentation spectra (MS2) impedes confident compound annotation in spatial metabolomics. Here, we describe spatial ion mobility-scheduled exhaustive fragmentation (SIMSEF), a dataset-dependent acquisition strategy that augments TIMS-MS imaging datasets with MS2 spectra. The fragmentation experiments are systematically distributed across the sample and scheduled for multiple collision energies per precursor ion. Extendable data processing and evaluation workflows are implemented into the open source software MZmine. The workflow and annotation capabilities are demonstrated on rat brain tissue thin sections, measured by matrix-assisted laser desorption/ionisation (MALDI)-TIMS-MS, where SIMSEF enables on-tissue compound annotation through spectral library matching and rule-based lipid annotation within MZmine and maps the (un)known chemical space by molecular networking. The SIMSEF algorithm and data analysis pipelines are open source and modular to provide a community resource.
    DOI:  https://doi.org/10.1038/s41467-023-43298-9
  11. FEBS Open Bio. 2023 Nov 20.
    Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses.
    Valeria Mannella, Linda Chaabane, Tamara Canu, Alan Zanardi, Sara Raia, Antonio Conti, Barbara Ferrini, Andrea Caricasole, Giovanna Musco, Massimo Alessio.
      Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional interaction of iron with the metabolism of lipids has been associated with several metabolic diseases, the role of Cp in adipose tissue metabolism and in the interplay between hepatocytes and adipocytes has been poorly investigated. We previously found that Cp-deficient (CpKO) mice become overweight and demonstrate adipose tissue accumulation together with liver steatosis during aging, suggestive of lipid dysmetabolism. In this work, we investigated the lipid alterations which occur during aging in adipose tissue and liver of CpKO and wild-type (WT) mice both in vivo and ex vivo. During aging of CpKO mice, we observed adipose tissue accumulation and liver lipid deposition, both of which are associated with macrophage infiltration. Liver lipid deposition was characterized by accumulation of triglycerides, fatty acids and ⍵-3 fatty acids, and by a switch from unsaturated to saturated fatty acids, which is characteristic of lipid storage. Liver steatosis was preceded by iron deposition and macrophage infiltration, and this was observed to be already occurring in younger CpKO mice. The accumulation of ⍵-3 fatty acids, which can only be acquired through diet, was associated with body weight increase in CpKO mice despite the food intake being equal to that of WT mice, thus underlining the alterations in lipid metabolism/catabolism in Cp-deficient animals.
    Keywords:  aceruloplasminemia; ceruloplasmin; magnetic resonance imaging; magnetic resonance spectroscopy; nuclear magnetic resonance; steatosis
    DOI:  https://doi.org/10.1002/2211-5463.13740
  12. Redox Biol. 2023 Nov 19. pii: S2213-2317(23)00366-X. [Epub ahead of print]68 102965
    Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain.
    Yang Luo, Laurent Chatre, Shaden Melhem, Zayana M Al-Dahmani, Natalie Z M Homer, Anneke Miedema, Leo E Deelman, Matthew R Groves, Martin Feelisch, Nicholas M Morton, Amalia Dolga, Harry van Goor.
      Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst-/- mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst-/- mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction.
    Keywords:  Antioxidant; Nrf2 signaling; Oxidative distress; Reactive species; Thiosulfate sulfurtransferase (TST)
    DOI:  https://doi.org/10.1016/j.redox.2023.102965
  13. Nat Metab. 2023 Nov 20.
    Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
    Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.
      Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00924-6
  14. FASEB J. 2023 Dec;37(12): e23316
    Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury.
    René M Roy, Ayed Allawzi, Nana Burns, Christina Sul, Victoria Rubio, Jessica Graham, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Christine U Vohwinkel.
      Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome-and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra-alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia-inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti-inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL-10, while decreasing IL-1 and IL-6 expression. Mice with ATII-specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co-cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti-inflammatory phenotype and dampens excessive inflammation in ALI.
    Keywords:  acute lung injury; acute respiratory distress syndrome; alveolar epithelium; alveolar macrophage; glycolysis; hypoxia-inducible factor; lactate
    DOI:  https://doi.org/10.1096/fj.202301722R
  15. Nat Commun. 2023 Nov 21. 14(1): 6763
    Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.
    Ryutaro Tamura, Yusuke Sabu, Tadahaya Mizuno, Seiya Mizuno, Satoshi Nakano, Mitsuyoshi Suzuki, Daiki Abukawa, Shunsaku Kaji, Yoshihiro Azuma, Ayano Inui, Tatsuya Okamoto, Seiichi Shimizu, Akinari Fukuda, Seisuke Sakamoto, Mureo Kasahara, Satoru Takahashi, Hiroyuki Kusuhara, Yoh Zen, Tomohiro Ando, Hisamitsu Hayashi.
      Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.
    DOI:  https://doi.org/10.1038/s41467-023-42424-x
  16. J Biol Chem. 2023 Nov 16. pii: S0021-9258(23)02501-2. [Epub ahead of print] 105473
    Human V-ATPase a-subunit isoforms bind specifically to distinct phosphoinositide phospholipids.
    Connie Mitra, Samuel Winkley, Patricia M Kane.
      V-ATPases are highly conserved multi-subunit enzymes that maintain the distinct pH of eukaryotic organelles. The integral membrane a-subunit is encoded by tissue- and organelle- specific isoforms, and its cytosolic N-terminal domain (aNT) modulates organelle specific regulation and targeting of V-ATPases. Organelle membranes have specific phosphatidylinositol phosphate (PIP) lipid enrichment linked to maintenance of organelle pH. In yeast, the aNT domains of the two a-subunit isoforms bind PIP lipids enriched in the organelle membranes where they reside; these interactions affect activity and regulatory properties of the V-ATPases containing each isoform. Humans have four a-subunit isoforms, and we hypothesize that the aNT domains of these isoforms will also bind to specific PIP lipids. The a1 and a2 isoforms of human V-ATPase a-subunits are localized to endolysosomes and Golgi, respectively. We determined that bacterially expressed Hua1NT and Hua2NT bind specifically to endolysosomal PIP lipids PI(3)P and PI(3,5)P2 and Golgi enriched PI(4)P, respectively. Despite the lack of canonical PIP binding sites, we identified potential binding sites in the HuaNT domains by sequence comparisons and existing subunit structures and models. We found that mutations at a similar location in the distal loops of both HuaNT isoforms compromise binding to their cognate PIP lipids, suggesting that these loops encode PIP specificity of the a-subunit isoforms. These data suggest a mechanism through which PIP lipid binding could stabilize and activate V-ATPases in distinct organelles.
    Keywords:  Golgi; V-ATPase; a-subunit isoforms; endosomes; liposomes; lysosomes; phosphoinositide
    DOI:  https://doi.org/10.1016/j.jbc.2023.105473
  17. Cancer Immunol Res. 2023 Nov 21.
    A metabolic axis of immune intractability.
    Dominique C Hinshaw, Meet Patel, Lalita A Shevde.
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  18. Sci Transl Med. 2023 Nov 22. 15(723): eadf9382
    Metaflammation in obesity and its therapeutic targeting.
    Michael W Schleh, Heather L Caslin, Jamie N Garcia, Mona Mashayekhi, Gitanjali Srivastava, Anna B Bradley, Alyssa H Hasty.
      Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.
    DOI:  https://doi.org/10.1126/scitranslmed.adf9382
  19. J Cell Biol. 2024 Jan 01. pii: e202305048. [Epub ahead of print]223(1):
    Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
    Anupama Tiwari, Arsalan Hashemiaghdam, Marissa A Laramie, Dario Maschi, Tristaan Haddad, Marion I Stunault, Carmen Bergom, Ali Javaheri, Vitaly Klyachko, Ghazaleh Ashrafi.
      Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.
    DOI:  https://doi.org/10.1083/jcb.202305048
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