bims-mepmim 2024-01-28 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–01–28
37 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.
Adipose-specific overexpression of human AGPAT2 in mice causes increased adiposity and mild hepatic dysfunction.
PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.
Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.
Ferredoxin 1 is essential for embryonic development and lipid homeostasis.
AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
Engineering peroxisomal biosynthetic pathways for maximization of triterpene production in Yarrowia lipolytica.
Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity.
Metabolic heterogeneity in cancer.
Cell surface RNAs control neutrophil recruitment.
EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
Targeting Src SH3 domain-mediated glycolysis of hepatic stellate cells suppresses transcriptome, myofibroblastic activation, and colorectal liver metastasis.
Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity.
Mitochondrial translocation of TFEB regulates complex I and inflammation.
Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity.
AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival.
Nutrient-derived signals regulate eosinophil adaptation to the small intestine.
Elongation factor 1A1 regulates metabolic substrate preference in mammalian cells.
Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts.
The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.
Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.
Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.
Exosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia.
G protein-coupled estrogen receptor 1 ameliorates nonalcoholic steatohepatitis through targeting AMPK-dependent signaling.
Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischemia-reperfusion injury by elevating plasma adiponectin.
Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice.
A spatiotemporal molecular atlas of the ovulating mouse ovary.
Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.
Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression.
Gut microbiome mediates ferroptosis resistance for colorectal cancer development.
The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.
Microbiota derived D-malate inhibits skeletal muscle growth and angiogenesis during aging via acetylation of Cyclin A.
Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.
Spatial Lipidomics of Coronary Atherosclerotic Plaque Development in a Familial Hypercholesterolemia Swine Model.
Sulfated bile acid is a host-derived ligand for MAIT cells.
CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance.

Cell Rep. 2024 Jan 23. pii: S2211-1247(24)00028-7. [Epub ahead of print]43(2): 113700

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.

Milton Pereira, Jonathan Liang, Joy Edwards-Hicks, Allison M Meadows, Christine Hinz, Sonia Liggi, Matthias Hepprich, Jonathan Mudry, Kim Han, Julian L Griffin, Iain Fraser, Michael N Sack, Christoph Hess, Clare E Bryant.

  Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Keywords:  CP: Immunology; CP: Metabolism; NLRP3; eicosanoids; inflammasome; inflammation; lipidomics; metaflammation; prostaglandins

DOI:  https://doi.org/10.1016/j.celrep.2024.113700
iScience. 2024 Jan 19. 27(1): 108653

Adipose-specific overexpression of human AGPAT2 in mice causes increased adiposity and mild hepatic dysfunction.

Anil K Agarwal, Katie Tunison, Goncalo Vale, Jeffrey G McDonald, Xilong Li, Jay D Horton, Abhimanyu Garg.

  AGPAT2, a critical enzyme involved in the biosynthesis of phospholipids and triacylglycerol (TAG), is highly expressed in adipose tissue (AT). Whether overexpression of AGPAT2 in AT will result in increased TAG synthesis (obesity) and its metabolic complications remains unknown. We overexpressed human AGPAT2 specifically in AT using the adiponectin promoter and report increased mass of subcutaneous, gonadal, and brown AT in wild-type mice. Unexpectedly, overexpression of hAGPAT2 did not change the pattern of phospholipid or TAG concentration of the AT depots. Although there is an increase in liver weight, plasma aspartate aminotransferase, and plasma insulin at various time points of the study, it did not result in significant liver dysfunction. Despite increased adiposity in the Tg-AT-hAGPAT2;mAgpat2+/+ mice, there was no significant increase in TAG concentration of AT. Therefore, this study suggests a role of AGPAT2 in the generation of AT, but not for adipocyte TAG synthesis.

Keywords:  Cell biology; Cellular physiology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.108653
Blood. 2024 Jan 25. pii: blood.2023022202. [Epub ahead of print]

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

Hao Gu, Chiqi Chen, Zhi-Shuai Hou, Xia-Di He, Shaozhen Xie, Jing Ni, Changli Qian, Xin Cheng, Tao Jiang, Ce Yang, Thomas M Roberts, Junke Zheng, Judith A Varner, Scott A Armstrong, Jean J Zhao.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

DOI: https://doi.org/10.1182/blood.2023022202
Mol Cell. 2024 Jan 17. pii: S1097-2765(24)00003-0. [Epub ahead of print]

Serine synthesis sustains macrophage IL-1β production via NAD+-dependent protein acetylation.

Chuanlong Wang, Qingyi Chen, Siyuan Chen, Lijuan Fan, Zhending Gan, Muyang Zhao, Lexuan Shi, Peng Bin, Guan Yang, Xihong Zhou, Wenkai Ren.

  Serine metabolism is involved in the fate decisions of immune cells; however, whether and how de novo serine synthesis shapes innate immune cell function remain unknown. Here, we first demonstrated that inflammatory macrophages have high expression of phosphoglycerate dehydrogenase (PHGDH, the rate-limiting enzyme of de novo serine synthesis) via nuclear factor κB signaling. Notably, the pharmacological inhibition or genetic modulation of PHGDH limits macrophage interleukin (IL)-1β production through NAD+ accumulation and subsequent NAD+-dependent SIRT1 and SIRT3 expression and activity. Mechanistically, PHGDH not only sustains IL-1β expression through H3K9/27 acetylation-mediated transcriptional activation of Toll-like receptor 4 but also supports IL-1β maturation via NLRP3-K21/22/24/ASC-K21/22/24 acetylation-mediated activation of the NLRP3 inflammasome. Moreover, mice with myeloid-specific depletion of Phgdh show alleviated inflammatory responses in lipopolysaccharide-induced systemic inflammation. This study reveals a network by which a metabolic enzyme, involved in de novo serine synthesis, mediates post-translational modifications and epigenetic regulation to orchestrate IL-1β production, providing a potential inflammatory disease target.

Keywords:  NAD(+); NLRP3; PHGDH; SIRT1; SIRT3; TLR4; acetylation; macrophage; serine

DOI:  https://doi.org/10.1016/j.molcel.2024.01.002
Elife. 2024 Jan 22. pii: e91656. [Epub ahead of print]13

Ferredoxin 1 is essential for embryonic development and lipid homeostasis.

Shakur Mohibi, Yanhong Zhang, Vivian Perng, Mingyi Chen, Jin Zhang, Xinbin Chen.

  Mammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored. In this study, we generated Fdx1-deficient mice and showed that knockout of both alleles of the Fdx1 gene led to embryonic lethality. We also showed that like Fdxr+/- mice, Fdx1+/- mice had a shorter life span and were prone to steatohepatitis. However, unlike Fdxr+/- mice, Fdx1+/- mice were not prone to spontaneous tumors. Additionally, we showed that FDX1 deficiency led to lipid droplet accumulation possibly via the ABCA1-SREBP1/2 pathway. Specifically, untargeted lipidomic analysis showed that FDX1 deficiency led to alterations in several classes of lipids, including cholesterol, triacylglycerides, acylcarnitines, ceramides, phospholipids and lysophospholipids. Taken together, our data indicate that FDX1 is essential for mammalian embryonic development and lipid homeostasis at both cellular and organismal levels.

Keywords:  cancer biology; mouse

DOI:  https://doi.org/10.7554/eLife.91656
Nat Commun. 2024 Jan 23. 15(1): 686

AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.

Taiqi Chen, Siyi Xie, Jie Cheng, Qiao Zhao, Hong Wu, Peng Jiang, Wenjing Du.

Many types of tumors feature aerobic glycolysis for meeting their increased energetic and biosynthetic demands. However, it remains still unclear how this glycolytic phenomenon is achieved and coordinated with other metabolic pathways in tumor cells in response to growth stimuli. Here we report that activation of AKT1 induces a metabolic switch to glycolysis from the mitochondrial metabolism via phosphorylation of cytoplasmic malic enzyme 2 (ME2), named ME2fl (fl means full length), favoring an enhanced glycolytic phenotype. Mechanistically, in the cytoplasm, AKT1 phosphorylates ME2fl at serine 9 in the mitochondrial localization signal peptide at the N-terminus, preventing its mitochondrial translocation. Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.

DOI: https://doi.org/10.1038/s41467-024-44772-8
Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2314798121

Engineering peroxisomal biosynthetic pathways for maximization of triterpene production in Yarrowia lipolytica.

Yongshuo Ma, Yi Shang, Gregory Stephanopoulos.

  Constructing efficient cell factories for product synthesis is frequently hampered by competing pathways and/or insufficient precursor supply. This is particularly evident in the case of triterpenoid biosynthesis in Yarrowia lipolytica, where squalene biosynthesis is tightly coupled to cytosolic biosynthesis of sterols essential for cell viability. Here, we addressed this problem by reconstructing the complete squalene biosynthetic pathway, starting from acetyl-CoA, in the peroxisome, thus harnessing peroxisomal acetyl-CoA pool and sequestering squalene synthesis in this organelle from competing cytosolic reactions. This strategy led to increasing the squalene levels by 1,300-fold relatively to native cytosolic synthesis. Subsequent enhancement of the peroxisomal acetyl-CoA supply by two independent approaches, 1) converting cellular lipid pool to peroxisomal acetyl-CoA and 2) establishing an orthogonal acetyl-CoA shortcut from CO2-derived acetate in the peroxisome, further significantly improved local squalene accumulation. Using these approaches, we constructed squalene-producing strains capable of yielding 32.8 g/L from glucose, and 31.6 g/L from acetate by employing a cofeeding strategy, in bioreactor fermentations. Our findings provide a feasible strategy for protecting intermediate metabolites that can be claimed by multiple reactions by engineering peroxisomes in Y. lipolytica as microfactories for the production of such intermediates and in particular acetyl-CoA-derived metabolites.

Keywords:  acetate metabolism; metabolic engineering; orthogonal pathway; peroxisome; triterpenoids

DOI:  https://doi.org/10.1073/pnas.2314798121
Nat Commun. 2024 Jan 20. 15(1): 633

Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity.

Xue Zhang, Shishir M Pant, Cecily C Ritch, Hsin-Yao Tang, Hongguang Shao, Harsh Dweep, Yao-Yu Gong, Rebekah Brooks, Patricia Brafford, Adam J Wolpaw, Yool Lee, Ashani Weeraratna, Amita Sehgal, Meenhard Herlyn, Andrew Kossenkov, David Speicher, Peter K Sorger, Sandro Santagata, Chi V Dang.

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10high to a Sox9high immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton.

DOI: https://doi.org/10.1038/s41467-024-44778-2
Nat Metab. 2024 Jan 24.

Metabolic heterogeneity in cancer.

Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.

Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.

DOI: https://doi.org/10.1038/s42255-023-00963-z
Cell. 2024 Jan 17. pii: S0092-8674(23)01443-5. [Epub ahead of print]

Cell surface RNAs control neutrophil recruitment.

Ningning Zhang, Wenwen Tang, Lidiane Torres, Xujun Wang, Yasmeen Ajaj, Li Zhu, Yi Luan, Hongyue Zhou, Yadong Wang, Dingyao Zhang, Vadim Kurbatov, Sajid A Khan, Priti Kumar, Andres Hidalgo, Dianqing Wu, Jun Lu.

  RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.

Keywords:  45S rRNA; E-selectin; Sidt1; Sidt2; peritonitis; snoRNA; tRNA

DOI:  https://doi.org/10.1016/j.cell.2023.12.033
Cancer Discov. 2024 Jan 25. OF1-OF22

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.

Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S Kuna, Kacie A Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M Kwong, Stellar Levy, Anna-Maria Globig, Matthew M Nobari, George Z Cheng, Sandra L Leibel, Robert J Homer, Reuben J Shaw, Christian M Metallo, Katerina Politi, Susan M Kaech.

The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
SIGNIFICANCE: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0434
Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.

Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.

  Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.

Keywords:  D. melanogaster; S. cerevisiae; cell biology; human

DOI:  https://doi.org/10.7554/eLife.84282
Hepatology. 2024 Jan 24.

Targeting Src SH3 domain-mediated glycolysis of hepatic stellate cells suppresses transcriptome, myofibroblastic activation, and colorectal liver metastasis.

Yuanguo Wang, Xianghu Wang, Bing Bai, Aurpita Shaha, Xipu He, Yingzi He, Zhenqing Ye, Vijay H Shah, Ningling Kang.

BACKGROUND AND AIMS: TGFβ1 induces hepatic stellate cell (HSC) activation into metastasis-promoting cancer-associated fibroblasts (CAFs), but how the process is fueled remains incompletely understood. We studied metabolic reprograming induced by TGFβ1 in HSCs.
APPROACHES AND RESULTS: Activation of cultured primary human HSCs was assessed by expression of myofibroblast markers. Glucose transporter 1 (Glut1) of murine HSC was disrupted by Cre /LoxP recombination. Plasma membrane (PM) Glut1 and glycolysis were studied by biotinylation assay and the Angilent Seahorse XFe96 Analyzer. Subcutaneous HSC/tumor co-implantation and portal vein injection of MC38 colorectal cancer cells into HSC-specific Glut1 knockout mice were performed to determine in vivo relevance. Transcriptome was obtained by RNA sequencing of HSCs and spatialomics with MC38 liver metastases. TGFβ1-induced CAF activation of HSCs was accompanied by elevation of PM Glut1, glucose uptake, and glycolysis. Targeting Glut1 or Src by shRNA, pharmacologic inhibition, or a Src SH3 domain deletion mutant abrogated TGFβ1-stimulated PM accumulation of Glut1, glycolysis, and CAF activation. Mechanistically, binding of Src SH3 domain to SH3BP5 led to a Src/SH3BP5/Rab11/Glut1 complex that activated Rab11-dependent Glut1 PM transport under TGFβ1 stimulation. Deleting the Src SH3 domain or targeting Glut1 of HSCs by shRNA or Cre /LoxP recombination suppressed CAF activation in mice and MC38 colorectal liver metastasis. Multi-omics revealed that Glut1 deficiency in HSCs/CAFs suppressed HSC expression of tumor-promoting factors and altered MC38 transcriptome, contributing to reduced MC38 liver metastases.
CONCLUSION: The Src SH3 domain-facilitated metabolic reprogramming induced by TGFβ1 represents a target to inhibit CAF activation and the pro-metastatic liver microenvironment.

DOI: https://doi.org/10.1097/HEP.0000000000000763
Nat Commun. 2024 Jan 24. 15(1): 682

Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity.

Colin Y C Lee, Bethany C Kennedy, Nathan Richoz, Isaac Dean, Zewen K Tuong, Fabrina Gaspal, Zhi Li, Claire Willis, Tetsuo Hasegawa, Sarah K Whiteside, David A Posner, Gianluca Carlesso, Scott A Hammond, Simon J Dovedi, Rahul Roychoudhuri, David R Withers, Menna R Clatworthy.

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7+ DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7+ DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7+ DCs co-localise with PD-1+CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells.

DOI: https://doi.org/10.1038/s41467-024-44787-1
EMBO Rep. 2024 Jan 23.

Mitochondrial translocation of TFEB regulates complex I and inflammation.

Chiara Calabrese, Hendrik Nolte, Melissa R Pitman, Raja Ganesan, Philipp Lampe, Raymond Laboy, Roberto Ripa, Julia Fischer, Ruhi Polara, Sameer Kumar Panda, Sandhya Chipurupalli, Saray Gutierrez, Daniel Thomas, Stuart M Pitson, Adam Antebi, Nirmal Robinson.

  TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Keywords:  LONP1; Metabolism; Mitochondria; Salmonella; TFEB

DOI:  https://doi.org/10.1038/s44319-024-00058-0
Nat Commun. 2024 Jan 24. 15(1): 683

Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity.

Isaac Dean, Colin Y C Lee, Zewen K Tuong, Zhi Li, Christopher A Tibbitt, Claire Willis, Fabrina Gaspal, Bethany C Kennedy, Veronika Matei-Rascu, Rémi Fiancette, Caroline Nordenvall, Ulrik Lindforss, Syed Murtuza Baker, Christian Stockmann, Veronika Sexl, Scott A Hammond, Simon J Dovedi, Jenny Mjösberg, Matthew R Hepworth, Gianluca Carlesso, Menna R Clatworthy, David R Withers.

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.

DOI: https://doi.org/10.1038/s41467-024-44789-z
JCI Insight. 2024 Jan 23. pii: e178502. [Epub ahead of print]

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival.

Collin Z Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E Dilts, Olivia K Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B Thorp, Xunrong Luo.

  Innate immune cells are important in the initiation and potentiation of alloimmunity in transplantation. Immediately upon organ anastomosis and reperfusion, recipient monocytes enter the graft from circulation and differentiate to inflammatory macrophages to promote allograft inflammation. However, factors that drive their differentiation to inflammatory macrophages are not understood. Here, we showed that the receptor tyrosine kinase AXL was a key driver of early intragraft differentiation of recipient infiltrating monocytes to inflammatory macrophages in the presence of allogeneic stimulation and cell-cell contact. In this context, the differentiated inflammatory macrophages were capable of efficient alloantigen presentation and allo-stimulation of T cells of the indirect pathway. Consequently, early and transient AXL inhibition with the pharmacological inhibitor bemcentinib resulted in a profound reduction of initial allograft inflammation and a significant prolongation of allograft survival in a murine heart transplant model. Our results support further investigation of AXL inhibition as part of an induction regimen for transplantation.

Keywords:  Immunology; Innate immunity; Macrophages; Organ transplantation; Transplantation

DOI:  https://doi.org/10.1172/jci.insight.178502
Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2316446121

Nutrient-derived signals regulate eosinophil adaptation to the small intestine.

Vassily I Kutyavin, Lisa L Korn, Ruslan Medzhitov.

  Eosinophils are well recognized as effector cells of type 2 immunity, yet they also accumulate in many tissues under homeostatic conditions. However, the processes that govern homeostatic eosinophil accumulation and tissue-specific adaptation, and their functional significance, remain poorly defined. Here, we investigated how eosinophils adapt to the small intestine (SI) microenvironment and the local signals that regulate this process. We observed that eosinophils gradually migrate along the crypt-villus axis, giving rise to a villus-resident subpopulation with a distinct transcriptional signature. Retinoic acid signaling was specifically required for maintenance of this subpopulation, while IL-5 was largely dispensable outside of its canonical role in eosinophil production. Surprisingly, we found that a high-protein diet suppressed the accumulation of villus-resident eosinophils. Purified amino acids were sufficient for this effect, which was a consequence of accelerated eosinophil turnover within the tissue microenvironment and was not due to altered development in the bone marrow. Our study provides insight into the process of eosinophil adaptation to the SI, highlighting its reliance on nutrient-derived signals.

Keywords:  eosinophils; inflammation; retinoic acid; small intestine

DOI:  https://doi.org/10.1073/pnas.2316446121
J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00060-7. [Epub ahead of print] 105684

Elongation factor 1A1 regulates metabolic substrate preference in mammalian cells.

Rachel B Wilson, Alexandra M Kozlov, Helia Hatam Tehrani, Jessica S Twumasi Ankrah, Yun Jin Chen, Matthew J Borrelli, Cynthia G Sawyez, Siddhant Maini, Trevor G Shepherd, Robert C Cumming, Dean H Betts, Nica M Borradaile.

Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis, but also has non-canonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient CHO-K1 (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells, and in wild type CHO-K1 and HepG2 cells treated with selective EEF1A inhibitors, didemnin B or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA sequencing revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2 (HK2), which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells.

DOI: https://doi.org/10.1016/j.jbc.2024.105684
J Proteome Res. 2024 Jan 24.

Data-Independent Acquisition Proteomics and N-Terminomics Methods Reveal Alterations in Mitochondrial Function and Metabolism in Ischemic-Reperfused Hearts.

Bridgette Hartley, Wesam Bassiouni, Andrej Roczkowsky, Richard Fahlman, Richard Schulz, Olivier Julien.

  Myocardial ischemia-reperfusion (IR) (stunning) injury triggers changes in the proteome and degradome of the heart. Here, we utilize quantitative proteomics and comprehensive degradomics to investigate the molecular mechanisms of IR injury in isolated rat hearts. The control group underwent aerobic perfusion, while the IR injury group underwent 20 min of ischemia and 30 min of reperfusion to induce a stunning injury. As MMP-2 activation has been shown to contribute to myocardial injury, hearts also underwent IR injury with ARP-100, an MMP-2-preferring inhibitor, to dissect the contribution of MMP-2 to IR injury. Using data-independent acquisition (DIA) and mass spectroscopy, we quantified 4468 proteins in ventricular extracts, whereby 447 proteins showed significant alterations among the three groups. We then used subtiligase-mediated N-terminomic labeling to identify more than a hundred specific cleavage sites. Among these protease substrates, 15 were identified following IR injury. We identified alterations in numerous proteins involved in mitochondrial function and metabolism following IR injury. Our findings provide valuable insights into the biochemical mechanisms of myocardial IR injury, suggesting alterations in reactive oxygen/nitrogen species handling and generation, fatty acid metabolism, mitochondrial function and metabolism, and cardiomyocyte contraction.

Keywords:  data-independent acquisition; degradomics; intracellular protease; ischemic heart disease; mass spectrometry; matrix metalloproteinase; proteolysis

DOI:  https://doi.org/10.1021/acs.jproteome.3c00754
Sci Rep. 2024 01 22. 14(1): 1899

The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.

John W R Kincaid, Debra Rimmington, John A Tadross, Irene Cimino, Ilona Zvetkova, Arthur Kaser, Paul Richards, Satish Patel, Stephen O'Rahilly, Anthony P Coll.

The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug's beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.

DOI: https://doi.org/10.1038/s41598-024-51866-2
ACS Nano. 2024 Jan 26.

Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.

Lingtong Meng, Jingpeng Yang, Yang Gao, Qinyan Cao, Shunjie Jiang, Yuyang Xiao, Haoran Wang, Wenzheng Liu, Ahu Yuan, Yanan Li, He Huang.

  Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.

Keywords:  autophagy; glucose metabolism; glutamine metabolism; metabolic plasticity; nanomedicine

DOI:  https://doi.org/10.1021/acsnano.3c10129
FEBS Lett. 2024 Jan 24.

Uncovering mechanisms of interorganelle lipid transport by enzymatic mass tagging.

Arun T John Peter, Benoit Kornmann.

  Lipid trafficking is critical for the biogenesis and expansion of organelle membranes. Lipid transport proteins (LTPs) have been proposed to facilitate lipid transport at contact sites between organelles. Despite the fundamental importance of LTPs in cell physiology, our knowledge on the mechanisms of interorganelle lipid distribution remains poor due to the scarcity of assays to monitor lipid flux in vivo. In this review, we highlight the recent development of a versatile method named METALIC (Mass tagging-Enabled Tracking of Lipids in Cells), which uses a combination of enzymatic mass tagging and mass spectrometry to track lipid flux between organelles inside living cells. We discuss the methodology, its distinct advantages, limitations as well as its potential to unearth the pipelines of lipid transport and LTP function in vivo.

Keywords:  CFAse; METALIC; cyclopropane fatty acid; lipid trafficking; lipid transport assay; lipid transport protein; lipidomics; mass tagging; membrane contact sites; phospholipid

DOI:  https://doi.org/10.1002/1873-3468.14810
Nat Commun. 2024 Jan 23. 15(1): 691

Exosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia.

Xiaolei Pei, Li Liu, Jieru Wang, Changyuan Guo, Qingqing Li, Jia Li, Qian Ren, Runzhi Ma, Yi Zheng, Yan Zhang, Li Liu, Danfeng Zheng, Pingzhang Wang, Ping Jiang, Xiaoming Feng, Erlie Jiang, Ying Wang, Sizhou Feng.

In pneumonia, the deficient or delayed pathogen clearance can lead to pathogen proliferation and subsequent overactive immune responses, inducing acute lung injury (ALI). While screening human genome coding genes using our peripheral blood cell chemotactic platform, we unexpectedly find SLP adaptor and CSK interacting membrane protein (SCIMP), a protein with neutrophil chemotactic activity secreted during ALI. However, the specific role of SCIMP in ALI remains unclear. In this study, we investigate the secretion of SCIMP in exosomes (SCIMPexo) by macrophages after bacterial stimulation, both in vitro and in vivo. We observe a significant increase in the levels of SCIMPexo in bronchoalveolar lavage fluid and serum of pneumonia patients. We also find that bronchial perfusion with SCIMPexo or SCIMP N-terminal peptides increases the survival rate of the ALI model. This occurs due to the chemoattraction and activation of peripheral neutrophils dependent on formyl peptide receptor 1/2 (FPR1/2). Conversely, exosome suppressors and FPR1/2 antagonists decrease the survival rate in the lethal ALI model. Scimp-deficient and Fpr1/2-deficient mice also have lower survival rates and shorter survival times than wild-type mice. However, bronchial perfusion of SCIMP rescues Scimp-deficient mice but not Fpr1/2-deficient mice. Collectively, our findings suggest that the macrophage-SCIMP-FPRs-neutrophil axis plays a vital role in the innate immune process underlying ALI.

DOI: https://doi.org/10.1038/s41467-024-44714-4
J Biol Chem. 2024 Jan 19. pii: S0021-9258(24)00037-1. [Epub ahead of print] 105661

G protein-coupled estrogen receptor 1 ameliorates nonalcoholic steatohepatitis through targeting AMPK-dependent signaling.

Longlong Li, Yao Yao, Yulei Wang, Ji Cao, Zhihao Jiang, Ying Yang, Huihui Wang, Haitian Ma.

  Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has emerged as a prevalent cause of liver cirrhosis and hepatocellular carcinoma, posing severe public health challenges worldwide. The incidence of NASH is highly correlated with an increased prevalence of obesity, insulin resistance, diabetes, and other metabolic diseases. Currently, no approved drugs specifically targeted for the therapies of NASH partially due to the unclear pathophysiological mechanisms. G protein-coupled estrogen receptor 1 (GPER1) is a membrane estrogen receptor involved in the development of metabolic diseases such as obesity and diabetes. However, the function of GPER1 in NAFLD/NASH progression remains unknown. Here, we show that GPER1 exerts a beneficial role in insulin resistance, hepatic lipid accumulation, oxidative stress, or inflammation in vivo and in vitro. In particular, we observed that the lipid accumulation, inflammatory response, fibrosis, or insulin resistance in mouse NAFLD/NASH models were exacerbated by hepatocyte-specific GPER1 knockout but obviously mitigated by hepatic GPER1 activation in female and male mice. Mechanistically, hepatic GPER1 activates AMP-activated protein kinase signaling by inducing cyclic AMP release, thereby exerting its protective effect. These data suggest that GPER1 may be a promising therapeutic target for NASH.

Keywords:  AMP-activated protein kinase; G protein-coupled estrogen receptor 1; Hepatocyte; Insulin resistance; Nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.jbc.2024.105661
Cardiovasc Res. 2024 Jan 22. pii: cvae017. [Epub ahead of print]

Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischemia-reperfusion injury by elevating plasma adiponectin.

Lin Fu, Jimin Du, David Furkert, Megan L Shipton, Xiaoqi Liu, Tim Aguirre, Alfred C Chin, Andrew M Riley, Barry V L Potter, Dorothea Fiedler, Xu Zhang, Yi Zhu, Chenglai Fu.

AIMS: Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest.
METHODS AND RESULTS: Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischemia-reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in WT but not adiponectin knockout mice attenuated myocardial ischemia-reperfusion injury.
CONCLUSIONS: Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.

DOI: https://doi.org/10.1093/cvr/cvae017
Nat Commun. 2024 Jan 20. 15(1): 627

Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice.

Xue Yang, Jianming Wang, Chun-Yuan Chang, Fan Zhou, Juan Liu, Huiting Xu, Maria Ibrahim, Maria Gomez, Grace L Guo, Hao Liu, Wei-Xing Zong, Fredric E Wondisford, Xiaoyang Su, Eileen White, Zhaohui Feng, Wenwei Hu.

Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.

DOI: https://doi.org/10.1038/s41467-024-44924-w
Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2317418121

A spatiotemporal molecular atlas of the ovulating mouse ovary.

Madhav Mantri, Hanxue Hannah Zhang, Emmanuel Spanos, Yi A Ren, Iwijn De Vlaminck.

  Ovulation is essential for reproductive success, yet the underlying cellular and molecular mechanisms are far from clear. Here, we applied high-resolution spatiotemporal transcriptomics to map out cell type- and ovulation stage-specific molecular programs as function of time during follicle maturation and ovulation in mice. Our analysis revealed dynamic molecular transitions within granulosa cell types that occur in tight coordination with mesenchymal cell proliferation. We identified molecular markers for the emerging cumulus cell fate during the preantral-to-antral transition. We describe transcriptional programs that respond rapidly to ovulation stimulation and those associated with follicle rupture, highlighting the prominent roles of apoptotic and metabolic pathways during the final stages of follicle maturation. We further report stage-specific oocyte-cumulus cell interactions and diverging molecular differentiation in follicles approaching ovulation. Collectively, this study provides insights into the cellular and molecular processes that regulate mouse ovarian follicle maturation and ovulation with important implications for advancing therapeutic strategies in reproductive medicine.

Keywords:  fertility; folliculogenesis; ovulation; reproductive biology; spatial transcriptomics

DOI:  https://doi.org/10.1073/pnas.2317418121
Cell Death Discov. 2024 Jan 20. 10(1): 39

Fatty acid metabolism of immune cells: a new target of tumour immunotherapy.

Sheng Zhang, Kebing Lv, Zhen Liu, Ran Zhao, Fei Li.

Metabolic competition between tumour cells and immune cells for limited nutrients is an important feature of the tumour microenvironment (TME) and is closely related to the outcome of tumour immune escape. A large number of studies have proven that tumour cells need metabolic reprogramming to cope with acidification and hypoxia in the TME while increasing energy uptake to support their survival. Among them, synthesis, oxidation and uptake of fatty acids (FAs) in the TME are important manifestations of lipid metabolic adaptation. Although different immune cell subsets often show different metabolic characteristics, various immune cell functions are closely related to fatty acids, including providing energy, providing synthetic materials and transmitting signals. In the face of the current situation of poor therapeutic effects of tumour immunotherapy, combined application of targeted immune cell fatty acid metabolism seems to have good therapeutic potential, which is blocked at immune checkpoints. Combined application of adoptive cell therapy and cancer vaccines is reflected. Therefore, it is of great interest to explore the role of fatty acid metabolism in immune cells to discover new strategies for tumour immunotherapy and improve anti-tumour immunity.

DOI: https://doi.org/10.1038/s41420-024-01807-9
JCI Insight. 2024 Jan 23. pii: e170428. [Epub ahead of print]9(2):

Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression.

Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu.

  Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Keywords:  Colorectal cancer; Endocrinology; Gastroenterology

DOI:  https://doi.org/10.1172/jci.insight.170428
Cancer Res. 2024 Jan 26.

Gut microbiome mediates ferroptosis resistance for colorectal cancer development.

Ruoxi Zhang, Rui Kang, Daolin Tang.

Colorectal cancer (CRC) is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in CRC development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes CRC by inhibiting ferroptosis, a type of non-apoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10) by apoptosis inducing factor mitochondria associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2, or ALDH1A3 reverses the inhibitory effect of IDA on ferroptosis and IDA-mediated tumor growth. Significantly, P. anaerobius is enriched in CRC patients, and supplementing IDA or P. anaerobius accelerates CRC progression in spontaneous or orthotopic mouse models. Taken together, these findings suggest that targeting P. anaerobius-mediated ferroptosis resistance emerges as a promising strategy to combat CRC development.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0275
Cancer Res. 2024 Jan 24.

The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.

Yongwei Su, Jenna L Carter, Xinyu Li, Yu Fukuda, Ashley Gray, John Lynch, Holly Edwards, Jun Ma, Patrick Schreiner, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Steven A Buck, Shondra M Pruett-Miller, Katie Hege Hurrish, Camenzind Robinson, Xinan Qiao, Shuang Liu, Shuangshuang Wu, Guan Wang, Jing Li, Joshua E Allen, Varun V Prabhu, Aaron D Schimmer, Dhananjay Joshi, Shiva Kalhor-Monfared, Iain D G Watson, Richard Marcellus, Methvin B Isaac, Rima Al-Awar, Jeffrey W Taub, Hai Lin, John D Schuetz, Yubin Ge.

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity. Deletion of OGDH, which encodes α-KGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for α-KGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced translation of MCL-1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitivity to ONC213 in vivo. Collectively these findings support further development of ONC213 for treating AML.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2659
EMBO Rep. 2024 Jan 22.

Microbiota derived D-malate inhibits skeletal muscle growth and angiogenesis during aging via acetylation of Cyclin A.

Penglin Li, Jinlong Feng, Hongfeng Jiang, Xiaohua Feng, Jinping Yang, Yexian Yuan, Zewei Ma, Guli Xu, Chang Xu, Canjun Zhu, Songbo Wang, Ping Gao, Gang Shu, Qingyan Jiang.

  Metabolites derived from the intestinal microbiota play an important role in maintaining skeletal muscle growth, function, and metabolism. Here, we found that D-malate (DMA) is produced by mouse intestinal microorganisms and its levels increase during aging. Moreover, we observed that dietary supplementation of 2% DMA inhibits metabolism in mice, resulting in reduced muscle mass, strength, and the number of blood vessels, as well as the skeletal muscle fiber type I/IIb ratio. In vitro assays demonstrate that DMA decreases the proliferation of vascular endothelial cells and suppresses the formation of blood vessels. In vivo, we further demonstrated that boosting angiogenesis by muscular VEGFB injection rescues the inhibitory effects of D-malate on muscle mass and fiber area. By transcriptomics analysis, we identified that the mechanism underlying the effects of DMA depends on the elevated intracellular acetyl-CoA content and increased Cyclin A acetylation rather than redox balance. This study reveals a novel mechanism by which gut microbes impair muscle angiogenesis and may provide a therapeutic target for skeletal muscle dysfunction in cancer or aging.

Keywords:  Acetylation; Angiogenesis; D-Malate; Skeletal Muscle; Vascular Endothelial Cells

DOI:  https://doi.org/10.1038/s44319-023-00028-y
Nat Metab. 2024 Jan 23.

Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.

Paula M Miotto, Chieh-Hsin Yang, Stacey N Keenan, William De Nardo, Cait A Beddows, Gio Fidelito, Garron T Dodd, Benjamin L Parker, Andrew F Hill, Paul R Burton, Kim Loh, Matthew J Watt.

Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.

DOI: https://doi.org/10.1038/s42255-023-00971-z
J Lipid Res. 2024 Jan 19. pii: S0022-2275(24)00009-9. [Epub ahead of print] 100504

Spatial Lipidomics of Coronary Atherosclerotic Plaque Development in a Familial Hypercholesterolemia Swine Model.

Nuria Slijkhuis, Francesca Razzi, Suze-Anne Korteland, Bram Heijs, Kim van Gaalen, Dirk J Duncker, Antonius F W van der Steen, Volkert van Steijn, Heleen M M van Beusekom, Gijs van Soest.

  Coronary atherosclerosis is caused by plaque build-up, with lipids playing a pivotal role in its progression. However, lipid composition and distribution within coronary atherosclerosis remain unknown. This study aims to characterize lipids and investigate differences in lipid composition across disease stages to aid in the understanding of disease progression. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize lipid distributions in coronary artery sections (n=17) from hypercholesterolemic swine. We performed histology on consecutive sections to classify the artery segments and to investigate colocalization between lipids and histological regions of interest in advanced plaque, including necrotic core and inflammatory cells. Segments were classified as healthy (n=6), mild (n=6), and advanced disease (n=5) artery segments. Multivariate data analysis was employed to find differences in lipid composition between the segment types, and the lipids' spatial distribution was investigated using non-negative matrix factorization (NMF). Through this process, MALDI-MSI detected 473 lipid-related features. NMF clustering described three components in positive ionization mode: triacylglycerides (TAG), phosphatidylcholines (PC), and cholesterol species. In negative ionization mode, two components were identified: one driven by phosphatidylinositol(PI)(38:4), and one driven by ceramide-phosphoethanolamine(36:1). Multivariate data analysis showed the association between advanced disease and specific lipid signatures like PC(O-40:5) and cholesterylester(CE)(18:2). Ether-linked phospholipids and LysoPC species were found to colocalize with necrotic core, and mostly CE, ceramide, and PI species colocalized with inflammatory cells. This study, therefore, uncovers distinct lipid signatures correlated with plaque development and their colocalization with necrotic core and inflammatory cells, enhancing our understanding of coronary atherosclerosis progression.

Keywords:  Atherosclerosis; dyslipidemias; familial hypercholesterolemia; histology; inflammation; lipids; lipids/chemistry; mass spectrometry imaging; plaque progression; vascular biology

DOI:  https://doi.org/10.1016/j.jlr.2024.100504
Sci Immunol. 2024 Jan 26. 9(91): eade6924

Sulfated bile acid is a host-derived ligand for MAIT cells.

Emi Ito, Shinsuke Inuki, Yoshihiro Izumi, Masatomo Takahashi, Yuki Dambayashi, Lisa Ciacchi, Wael Awad, Ami Takeyama, Kensuke Shibata, Shotaro Mori, Jeffrey Y W Mak, David P Fairlie, Takeshi Bamba, Eri Ishikawa, Masamichi Nagae, Jamie Rossjohn, Sho Yamasaki.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue-derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.

DOI: https://doi.org/10.1126/sciimmunol.ade6924
Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2318534121

CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance.

Allison Banuelos, Allison Zhang, Hala Berouti, Michelle Baez, Leyla Yılmaz, Nardin Georgeos, Kristopher D Marjon, Masanori Miyanishi, Irving L Weissman.

  The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.

Keywords:  CD47 blockade; CXCR2; macrophages; myeloid-derived suppressor cells; tumor immunology

DOI:  https://doi.org/10.1073/pnas.2318534121