bims-mepmim 2024-05-05 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–05–05
nineteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.
Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.
A model of mitochondrial superoxide production during ischaemia-reperfusion injury for therapeutic development and mechanistic understanding.
Dietary dicarboxylic acids provide a non-storable alternative fat source that protects mice against obesity.
Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.
Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome.
Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.
Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.
Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.
Coordinated chemokine expression defines macrophage subsets across tissues.
The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression.
Spatial Transcriptomics unravels palmitoylation and zonation-dependent gene regulation by AEG-1 in mouse liver.
Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
CD74 supports accumulation and function of regulatory T cells in tumors.
ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.
Multimodal decoding of human liver regeneration.
Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Cell Rep. 2024 Apr 27. pii: S2211-1247(24)00497-2. [Epub ahead of print]43(5): 114169

Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.

Derek Lee, Abigail M Benvie, Benjamin M Steiner, Nikolai J Kolba, Josie G Ford, Sean M McCabe, Yuwei Jiang, Daniel C Berry.

  Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

Keywords:  CP: Immunology; CP: Metabolism; Cxcl2; brown adipocytes; macrophage; smooth muscle cells; sympathetic innervation; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2024.114169
Nat Commun. 2024 Apr 27. 15(1): 3593

Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.

Meirion Raymant, Yuliana Astuti, Laura Alvaro-Espinosa, Daniel Green, Valeria Quaranta, Gaia Bellomo, Mark Glenn, Vatshala Chandran-Gorner, Daniel H Palmer, Christopher Halloran, Paula Ghaneh, Neil C Henderson, Jennifer P Morton, Manuel Valiente, Ainhoa Mielgo, Michael C Schmid.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

DOI: https://doi.org/10.1038/s41467-024-47949-3
Redox Biol. 2024 Apr 24. pii: S2213-2317(24)00137-X. [Epub ahead of print]72 103161

A model of mitochondrial superoxide production during ischaemia-reperfusion injury for therapeutic development and mechanistic understanding.

Annabel Sorby-Adams, Tracy A Prime, Jan Lj Miljkovic, Hiran A Prag, Thomas Krieg, Michael P Murphy.

  Ischaemia-reperfusion (IR) injury is the paradoxical consequence of the rapid restoration of blood flow to an ischaemic organ. Although reperfusion is essential for tissue survival in conditions such as myocardial infarction and stroke, the excessive production of mitochondrial reactive oxygen species (ROS) upon reperfusion initiates the oxidative damage that underlies IR injury, by causing cell death and inflammation. This ROS production is caused by an accumulation of the mitochondrial metabolite succinate during ischaemia, followed by its rapid oxidation upon reperfusion by succinate dehydrogenase (SDH), driving superoxide production at complex I by reverse electron transport. Inhibitors of SDH, such as malonate, show therapeutic potential by decreasing succinate oxidation and superoxide production upon reperfusion. To better understand the mechanism of mitochondrial ROS production upon reperfusion and to assess potential therapies, we set up an in vitro model of IR injury. For this, isolated mitochondria were incubated anoxically with succinate to mimic ischaemia and then rapidly reoxygenated to replicate reperfusion, driving a burst of ROS formation. Using this system, we assess the factors that contribute to the magnitude of mitochondrial ROS production in heart, brain, and kidney mitochondria, as well as screening for inhibitors of succinate oxidation with therapeutic potential.

Keywords:  Complex I; Ischaemia-reperfusion injury; Malonate; Mitochondria; Reverse electron transport; Succinate

DOI:  https://doi.org/10.1016/j.redox.2024.103161
J Clin Invest. 2024 Apr 30. pii: e174186. [Epub ahead of print]

Dietary dicarboxylic acids provide a non-storable alternative fat source that protects mice against obesity.

Eric S Goetzman, Bob B Zhang, Yuxun Zhang, Sivakama S Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J Solo, Alexandra V Schmidt, Adam C Richert, Steven J Mullett, Stacy L Gelhaus, Krithika S Rao, Sruti S Shiva, Katherine E Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F Dobrowolski, Birgit Schilling.

  Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.

Keywords:  Fatty acid oxidation; Metabolism; Mitochondria; Obesity

DOI:  https://doi.org/10.1172/JCI174186
Nat Metab. 2024 May 02.

Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.

Hu Wang, Jiaxing Wang, Hao Cui, Chenyu Fan, Yuzhou Xue, Huiying Liu, Hui Li, Jianping Li, Houhua Li, Ying Sun, Wengong Wang, Jiangping Song, Changtao Jiang, Ming Xu.

Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.

DOI: https://doi.org/10.1038/s42255-024-01036-5
Cancer Discov. 2024 Apr 17. OF1-OF22

Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.
SIGNIFICANCE: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0426
Redox Biol. 2024 Apr 27. pii: S2213-2317(24)00115-0. [Epub ahead of print]73 103139

SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome.

Ramon Cueto, Wen Shen, Lu Liu, Xianwei Wang, Sheng Wu, Sadia Mohsin, Ling Yang, Mohsin Khan, Wenhui Hu, Nathaniel Snyder, Qinghua Wu, Yong Ji, Xiao-Feng Yang, Hong Wang.

  In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

Keywords:  Hyperhomocysteinemia; Metabolic syndrome; Redox; S-Adenosyl-homocysteine (SAH); Serine; Taurine

DOI:  https://doi.org/10.1016/j.redox.2024.103139
EMBO Mol Med. 2024 Apr 29.

Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression.

Sara Clerici, Christine Podrini, Davide Stefanoni, Gianfranco Distefano, Laura Cassina, Maria Elena Steidl, Laura Tronci, Tamara Canu, Marco Chiaravalli, Daniel Spies, Thomas A Bell, Ana Sh Costa, Antonio Esposito, Angelo D'Alessandro, Christian Frezza, Angela Bachi, Alessandra Boletta.

  Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Keywords:  ADPKD; Antisense Oligonucleotides; Glutamine Metabolism; Glycolysis; Metabolic Reprogramming

DOI:  https://doi.org/10.1038/s44321-024-00071-9
Sci Immunol. 2024 May 03. 9(95): eadk0865

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Rui Li, Yanting Lei, Ayman Rezk, Diego A Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C Goldstein, Brenda L Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

DOI: https://doi.org/10.1126/sciimmunol.adk0865
J Biol Chem. 2024 Apr 26. pii: S0021-9258(24)01829-5. [Epub ahead of print] 107328

Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity.

Debarun Patra, Palla Ramprasad, Shivam Sharma, Upalabdha Dey, Vinod Kumar, Satpal Singh, Suman Dasgupta, Aditya Kumar, Kulbhushan Tikoo, Durba Pal.

  Management of chronic obesity-associated metabolic disorders is a key challenge for biomedical researchers. During chronic obesity, visceral adipose tissue (VAT) undergoes substantial transformation characterized by a unique lipid-rich hypoxic AT microenvironment (ATenv) which plays a crucial role in VAT dysfunction, leading to insulin resistance (IR) and type 2 diabetes(T2D). Here, we demonstrate that obese ATenv triggers the release of miR-210-3p microRNA-loaded extracellular vesicles (EVs) from adipose tissue macrophages (ATMs), which disseminate miR-210-3p to neighboring adipocytes, skeletal muscle cells, and hepatocytes through paracrine and endocrine actions, thereby influencing insulin sensitivity. Moreover, EVs collected from Dicer-silenced miR-210-3p-overexpressed bone marrow-derived macrophages (BMDMs), induce glucose intolerance and IR in lean mice. Mechanistically, miR-210-3p interacts with the 3'-UTR of GLUT4 mRNA and silences its expression, compromising cellular glucose uptake and insulin sensitivity. Therapeutic inhibition of miR-210-3p in VAT notably rescues high-fat diet (HFD)-fed mice from obesity-induced systemic glucose intolerance. Thus, targeting ATM-specific miR-210-3p during obesity could be a promising strategy for managing IR and T2D.

Keywords:  Adipose tissue microenvironment; Extracellular vesicles; GLUT4; Insulin resistance; Obesity; miR-210-3p

DOI:  https://doi.org/10.1016/j.jbc.2024.107328
Nat Immunol. 2024 May 02.

Coordinated chemokine expression defines macrophage subsets across tissues.

Xin Li, Arlind B Mara, Shawn C Musial, Fred W Kolling, Sophie L Gibbings, Nikita Gerebtsov, Claudia V Jakubzick.

Lung-resident macrophages, which include alveolar macrophages and interstitial macrophages (IMs), exhibit a high degree of diversity, generally attributed to different activation states, and often complicated by the influx of monocytes into the pool of tissue-resident macrophages. To gain a deeper insight into the functional diversity of IMs, here we perform comprehensive transcriptional profiling of resident IMs and reveal ten distinct chemokine-expressing IM subsets at steady state and during inflammation. Similar IM subsets that exhibited coordinated chemokine signatures and differentially expressed genes were observed across various tissues and species, indicating conserved specialized functional roles. Other macrophage types shared specific IM chemokine profiles, while also presenting their own unique chemokine signatures. Depletion of CD206hi IMs in Pf4creR26EYFP+DTR and Pf4creR26EYFPCx3cr1DTR mice led to diminished inflammatory cell recruitment, reduced tertiary lymphoid structure formation and fewer germinal center B cells in models of allergen- and infection-driven inflammation. These observations highlight the specialized roles of IMs, defined by their coordinated chemokine production, in regulating immune cell influx and organizing tertiary lymphoid tissue architecture.

DOI: https://doi.org/10.1038/s41590-024-01826-9
Immunol Rev. 2024 Apr 29.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.

Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu.

  White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

Keywords:  immunity; macrophage; metabolism; obesity; white adipose tissue

DOI:  https://doi.org/10.1111/imr.13338
Redox Biol. 2024 Apr 27. pii: S2213-2317(24)00146-0. [Epub ahead of print]73 103170

Non-esterified fatty acid palmitate facilitates oxidative endoplasmic reticulum stress and apoptosis of β-cells by upregulating ERO-1α expression.

Sarah Sharifi, Tomoko Yamamoto, Andre Zeug, Matthias Elsner, Edward Avezov, Ilir Mehmeti.

  Adipose tissue-derived non-esterified saturated long-chain fatty acid palmitate (PA) decisively contributes to β-cell demise in type 2 diabetes mellitus in part through the excessive generation of hydrogen peroxide (H2O2). The endoplasmic reticulum (ER) as the primary site of oxidative protein folding could represent a significant source of H2O2. Both ER-oxidoreductin-1 (ERO-1) isoenzymes, ERO-1α and ERO-1β, catalyse oxidative protein folding within the ER, generating equimolar amounts of H2O2 for every disulphide bond formed. However, whether ERO-1-derived H2O2 constitutes a potential source of cytotoxic luminal H2O2 under lipotoxic conditions is still unknown. Here, we demonstrate that both ERO-1 isoforms are expressed in pancreatic β-cells, but interestingly, PA only significantly induces ERO-1α. Its specific deletion significantly attenuates PA-mediated oxidative ER stress and subsequent β-cell death by decreasing PA-mediated ER-luminal and mitochondrial H2O2 accumulation, by counteracting the dysregulation of ER Ca2+ homeostasis, and by mitigating the reduction of mitochondrial membrane potential and lowered ATP content. Moreover, ablation of ERO-1α alleviated PA-induced hyperoxidation of the ER redox milieu. Importantly, ablation of ERO-1α did not affect the insulin secretory capacity, the unfolded protein response, or ER redox homeostasis under steady-state conditions. The involvement of ERO-1α-derived H2O2 in PA-mediated β-cell lipotoxicity was corroborated by the overexpression of a redox-active ERO-1α underscoring the proapoptotic activity of ERO-1α in pancreatic β-cells. Overall, our findings highlight the critical role of ERO-1α-derived H2O2 in lipotoxic ER stress and β-cell failure.

Keywords:  ER oxidoreductin-1α; Hydrogen peroxide; Lipotoxicity; Palmitate; Type 2 diabetes; β-cell death

DOI:  https://doi.org/10.1016/j.redox.2024.103170
J Biol Chem. 2024 Apr 25. pii: S0021-9258(24)01823-4. [Epub ahead of print] 107322

Spatial Transcriptomics unravels palmitoylation and zonation-dependent gene regulation by AEG-1 in mouse liver.

Alissa Saverino, Xufeng Qu, Rachel G Mendoza, Suchismita Raha, Debashri Manna, Ali Gawi Ermi, Mark A Subler, Jolene J Windle, Jinze Liu, Devanand Sarkar.

Obesity-induced metabolic dysfunction-associated steatohepatitis (MASH) leads to hepatocellular carcinoma (HCC). Astrocyte-elevated gene-1/Metadherin (AEG-1/MTDH) plays a key role in promoting MASH and HCC. AEG-1 is palmitoylated at residue cysteine 75 (Cys75) and a knock-in mouse representing mutated Cys75 to serine (AEG-1-C75S) showed activation of MASH- and HCC-promoting gene signature when compared to wild-type littermates (AEG-1-WT). The liver consists of 3 zones, periportal, midlobular and pericentral, and zone-specific dysregulated gene expression impairs metabolic homeostasis in the liver, contributing to MASH and HCC. Here, to elucidate how palmitoylation influences AEG-1-mediated gene regulation in regards to hepatic zonation, we performed spatial transcriptomics (ST) in the livers of AEG-1-WT and AEG-1-C75S littermates. ST identified six different clusters in livers and using zone- and cell type-specific markers we attributed specific zones and cell types to specific clusters. Ingenuity Pathway Analysis (IPA) of differentially expressed genes in each cluster unraveled activation of pro-inflammatory and MASH- and HCC-promoting pathways, mainly in periportal and pericentral hepatocytes, in AEG-1-C75S liver compared to AEG-1-WT. Interestingly, in AEG-1-C75S liver, the midlobular zone exhibited widespread inhibition of xenobiotic metabolism pathways and inhibition of PXR/RXR and LXR/RXR activation, vs AEG-1-WT. In conclusion, AEG-1-C75S mutant exhibited zone-specific differential gene expression, which might contribute to metabolic dysfunction and dysregulated drug metabolism leading to MASH and HCC.

DOI: https://doi.org/10.1016/j.jbc.2024.107322
Cell Rep. 2024 Apr 30. pii: S2211-1247(24)00470-4. [Epub ahead of print]43(5): 114142

Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.

Zihan Yu, Xianju Li, Yanni Quan, Jiawen Chen, Jiarui Liu, Nairen Zheng, Shuwen Liu, Yini Wang, Wanlin Liu, Chen Qiu, Yi Wang, Ruimao Zheng, Jun Qin.

  Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

Keywords:  CP: Metabolism; brown adipocyte; itaconate; obesity; proteomics; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2024.114142
Nat Commun. 2024 May 03. 15(1): 3749

CD74 supports accumulation and function of regulatory T cells in tumors.

Elisa Bonnin, Maria Rodrigo Riestra, Federico Marziali, Rafael Mena Osuna, Jordan Denizeau, Mathieu Maurin, Juan Jose Saez, Mabel Jouve, Pierre-Emmanuel Bonté, Wilfrid Richer, Fabien Nevo, Sebastien Lemoine, Nicolas Girard, Marine Lefevre, Edith Borcoman, Anne Vincent-Salomon, Sylvain Baulande, Helene D Moreau, Christine Sedlik, Claire Hivroz, Ana-Maria Lennon-Duménil, Jimena Tosello Boari, Eliane Piaggio.

Regulatory T cells (Tregs) are plastic cells playing a pivotal role in the maintenance of immune homeostasis. Tregs actively adapt to the microenvironment where they reside; as a consequence, their molecular and functional profiles differ among tissues and pathologies. In tumors, the features acquired by Tregs remains poorly characterized. Here, we observe that human tumor-infiltrating Tregs selectively overexpress CD74, the MHC class II invariant chain. CD74 has been previously described as a regulator of antigen-presenting cell biology, however its function in Tregs remains unknown. CD74 genetic deletion in human primary Tregs reveals that CD74KO Tregs exhibit major defects in the organization of their actin cytoskeleton and intracellular organelles. Additionally, intratumoral CD74KO Tregs show a decreased activation, a drop in Foxp3 expression, a low accumulation in the tumor, and consistently, they are associated with accelerated tumor rejection in preclinical models in female mice. These observations are unique to tumor conditions as, at steady state, CD74KO-Treg phenotype, survival, and suppressive capacity are unaffected in vitro and in vivo. CD74 therefore emerges as a specific regulator of tumor-infiltrating Tregs and as a target to interfere with Treg anti-tumor activity.

DOI: https://doi.org/10.1038/s41467-024-47981-3
Circulation. 2024 Apr 29.

ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.

Yang Lin, Chang-Hyun Gil, Kimihiko Banno, Masataka Yokoyama, Matthew Wingo, Ellen Go, Nutan Prasain, Ying Liu, Takashi Hato, Hisamichi Naito, Taku Wakabayashi, Musia Sominskaia, Meng Gao, Kevin Chen, Fuqiang Geng, Jesus Maria Gomez Salinero, Sisi Chen, W Christopher Shelley, Momoko Yoshimoto, Sergio Li Calzi, Michael P Murphy, Kyoji Horie, Maria B Grant, Ryan Schreiner, David Redmond, David P Basile, Shahin Rafii, Mervin C Yoder.

   BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive.
METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs.
RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs.
CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.

Keywords:  angiogenesis; blood vessels; developmental biology; endothelial cells

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.061833
Nature. 2024 May 01.

Multimodal decoding of human liver regeneration.

K P Matchett, J R Wilson-Kanamori, J R Portman, C A Kapourani, F Fercoq, S May, E Zajdel, M Beltran, E F Sutherland, J B G Mackey, M Brice, G C Wilson, S J Wallace, L Kitto, N T Younger, R Dobie, D J Mole, G C Oniscu, S J Wigmore, P Ramachandran, C A Vallejos, N O Carragher, M M Saeidinejad, A Quaglia, R Jalan, K J Simpson, T J Kendall, J A Rule, W M Lee, M Hoare, C J Weston, J C Marioni, S A Teichmann, T G Bird, L M Carlin, N C Henderson.

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

DOI: https://doi.org/10.1038/s41586-024-07376-2
Cancer Immunol Res. 2024 May 03.

Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.

Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif.

Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-1105