bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–03–24
sixteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation.
  2. Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.
  3. The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
  4. Activation of GPR81 by lactate drives tumour-induced cachexia.
  5. Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.
  6. Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
  7. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
  8. Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
  9. Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy.
  10. Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.
  11. Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis.
  12. MemPrep, a new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress.
  13. Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment.
  14. ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype.
  15. Visualizing mitochondrial heme flow through GAPDH in living cells and its regulation by NO.
  16. Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.
  1. J Exp Med. 2024 May 06. pii: e20232148. [Epub ahead of print]221(5):
    Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation.
    JRI Live Cell Bank
      Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, the inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared with controls, implicating this diet-microbiota-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.
    DOI:  https://doi.org/10.1084/jem.20232148
  2. Nat Chem Biol. 2024 Mar 20.
    Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.
    Roshan Kumar, Victor Vitvitsky, Apichaya Sethaudom, Rashi Singhal, Sumeet Solanki, Sydney Alibeckoff, Harrison L Hiraki, Hannah N Bell, Anthony Andren, Brendon M Baker, Costas A Lyssiotis, Yatrik M Shah, Ruma Banerjee.
      Angiogenic programming in the vascular endothelium is a tightly regulated process for maintaining tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Here, we report that hypoxic upregulation of ·NO in endothelial cells reprograms the transsulfuration pathway to increase biogenesis of hydrogen sulfide (H2S), a proangiogenic metabolite. However, decreased H2S oxidation due to sulfide quinone oxidoreductase (SQOR) deficiency synergizes with hypoxia, inducing a reductive shift and limiting endothelial proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body (WBCreSqorfl/fl) and endothelial-specific (VE-cadherinCre-ERT2Sqorfl/fl) Sqor-knockout mice exhibit lower mass and angiogenesis than control mice. WBCreSqorfl/fl mice also exhibit decreased muscle angiogenesis following femoral artery ligation compared to control mice. Collectively, our data reveal the molecular intersections between H2S, O2 and ·NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization.
    DOI:  https://doi.org/10.1038/s41589-024-01583-8
  3. J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):
    The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.
    Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.
      Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202302069
  4. Nat Metab. 2024 Mar 18.
    Activation of GPR81 by lactate drives tumour-induced cachexia.
    Xidan Liu, Shijin Li, Qionghua Cui, Bujing Guo, Wanqiu Ding, Jie Liu, Li Quan, Xiaochuan Li, Peng Xie, Li Jin, Ye Sheng, Wenxin Chen, Kai Wang, Fanxin Zeng, Yifu Qiu, Changlu Liu, Yan Zhang, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.
      Cachexia affects 50-80% of patients with cancer and accounts for 20% of cancer-related death, but the underlying mechanism driving cachexia remains elusive. Here we show that circulating lactate levels positively correlate with the degree of body weight loss in male and female patients suffering from cancer cachexia, as well as in clinically relevant mouse models. Lactate infusion per se is sufficient to trigger a cachectic phenotype in tumour-free mice in a dose-dependent manner. Furthermore, we demonstrate that adipose-specific G-protein-coupled receptor (GPR)81 ablation, similarly to global GPR81 deficiency, ameliorates lactate-induced or tumour-induced adipose and muscle wasting in male mice, revealing adipose GPR81 as the major mediator of the catabolic effects of lactate. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the well-established protein kinase A catabolic pathway, but it is mediated by a signalling cascade sequentially activating Gi-Gβγ-RhoA/ROCK1-p38. These findings highlight the therapeutic potential of targeting GPR81 for the treatment of this life-threatening complication of cancer.
    DOI:  https://doi.org/10.1038/s42255-024-01011-0
  5. Nat Metab. 2024 Mar 18.
    Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.
    Barry Scott, Emily A Day, Katie L O'Brien, John Scanlan, Grace Cromwell, Aine Ni Scannail, Marie E McDonnell, David K Finlay, Lydia Lynch.
      Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.
    DOI:  https://doi.org/10.1038/s42255-024-01018-7
  6. Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00176-X. [Epub ahead of print]
    Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.
    Tristen Wright, Meghan E Turnis, Christy R Grace, Xiao Li, Lauren A Brakefield, Yong-Dong Wang, Haiyan Xu, Ewa Kaminska, Leslie K Climer, Tresor O Mukiza, Chi-Lun Chang, Tudor Moldoveanu, Joseph T Opferman.
      MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.
    Keywords:  MCL-1; acyl-coenzyme A synthetase; apoptosis; fatty acid; metabolism; mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.035
  7. Nat Metab. 2024 Mar 19.
    Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
    Mathieu Membrez, Eugenia Migliavacca, Stefan Christen, Keisuke Yaku, Jennifer Trieu, Alaina K Lee, Francesco Morandini, Maria Pilar Giner, Jade Stiner, Mikhail V Makarov, Emma S Garratt, Maria F Vasiloglou, Lucie Chanvillard, Emilie Dalbram, Amy M Ehrlich, José Luis Sanchez-Garcia, Carles Canto, Leonidas G Karagounis, Jonas T Treebak, Marie E Migaud, Ramin Heshmat, Farideh Razi, Neerja Karnani, Afshin Ostovar, Farshad Farzadfar, Stacey K H Tay, Matthew J Sanders, Karen A Lillycrop, Keith M Godfrey, Takashi Nakagawa, Sofia Moco, René Koopman, Gordon S Lynch, Vincenzo Sorrentino, Jerome N Feige.
      Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.
    DOI:  https://doi.org/10.1038/s42255-024-00997-x
  8. Nat Commun. 2024 Mar 18. 15(1): 1878
    Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver.
    Ana Belén Plata-Gómez, Lucía de Prado-Rivas, Alba Sanz, Nerea Deleyto-Seldas, Fernando García, Celia de la Calle Arregui, Camila Silva, Eduardo Caleiras, Osvaldo Graña-Castro, Elena Piñeiro-Yáñez, Joseph Krebs, Luis Leiva-Vega, Javier Muñoz, Ajay Jain, Guadalupe Sabio, Alejo Efeyan.
      The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations. Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets. Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.
    DOI:  https://doi.org/10.1038/s41467-024-46032-1
  9. Cell Metab. 2024 Mar 13. pii: S1550-4131(24)00061-5. [Epub ahead of print]
    Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy.
    Haikuo Li, Dian Li, Nicolas Ledru, Qiao Xuanyuan, Haojia Wu, Amish Asthana, Lori N Byers, Stefan G Tullius, Giuseppe Orlando, Sushrut S Waikar, Benjamin D Humphreys.
      A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct kidney anatomical regions. We generated transcriptomes of 446,267 cells and chromatin accessibility profiles of 401,875 cells and developed a package to analyze 408,218 spatially resolved metabolomes. We find that the same cell type, including thin limb, thick ascending limb loop of Henle and principal cells, display distinct transcriptomic, chromatin accessibility, and metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene profiles revealed non-overlapping metabolic signatures between nephron segments and dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating multimodal omics with clinical data identified PLEKHA1 as a disease marker, and its in vitro knockdown increased gene expression in PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying the human kidney anatomy.
    Keywords:  MALDI-MS; SHARE-seq; acute kidney injury; anatomy; chronic kidney disease; lipid metabolism; metabolism; multiomics; single-cell combinatorial indexing; spatial metabolomics
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.015
  10. FASEB J. 2024 Mar 31. 38(6): e23505
    Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.
    Nikhil Pal, Animesh Acharjee, Zsuzsanna Ament, Tim Dent, Arash Yavari, Masliza Mahmod, Rina Ariga, James West, Violetta Steeples, Mark Cassar, Neil J Howell, Helen Lockstone, Kate Elliott, Parisa Yavari, William Briggs, Michael Frenneaux, Bernard Prendergast, Jeremy S Dwight, Rajesh Kharbanda, Hugh Watkins, Houman Ashrafian, Julian L Griffin.
      Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
    Keywords:  cardiac gradient; cardiac metabolism; ischemic heart disease; metabolomics; precision medicine
    DOI:  https://doi.org/10.1096/fj.202301710RR
  11. Cell Rep. 2024 Mar 15. pii: S2211-1247(24)00295-X. [Epub ahead of print]43(3): 113967
    Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis.
    Anna Carey, Katie Nguyen, Pranathi Kandikonda, Victor Kruglov, Claire Bradley, Korbyn J V Dahlquist, Stephanie Cholensky, Whitney Swanson, Vladimir P Badovinac, Thomas S Griffith, Christina D Camell.
      Non-canonical lipolysis induced by inflammatory cytokines or Toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging due to factors including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation; however, the extent to which the non-canonical pathway of lipolysis is active and impacted by immune cells during aging remains unclear. Therefore, we aimed to define the extent to which immune cells from old mice influence non-canonical lipolysis during sepsis. We identified age-associated impairments of non-canonical lipolysis and an accumulation of dysfunctional B1 B cells in the visceral white adipose tissue (vWAT) of old mice. Lifelong deficiency of B cells results in restored non-canonical lipolysis and reductions in pro-inflammatory macrophage populations. Our study suggests that targeting the B cell-macrophage signaling axis may resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.
    Keywords:  CP: Immunology; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.113967
  12. EMBO J. 2024 Mar 15.
    MemPrep, a new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress.
    John Reinhard, Leonhard Starke, Christian Klose, Per Haberkant, Henrik Hammarén, Frank Stein, Ofir Klein, Charlotte Berhorst, Heike Stumpf, James P Sáenz, Jochen Hub, Maya Schuldiner, Robert Ernst.
      Biological membranes have a stunning ability to adapt their composition in response to physiological stress and metabolic challenges. Little is known how such perturbations affect individual organelles in eukaryotic cells. Pioneering work has provided insights into the subcellular distribution of lipids in the yeast Saccharomyces cerevisiae, but the composition of the endoplasmic reticulum (ER) membrane, which also crucially regulates lipid metabolism and the unfolded protein response, remains insufficiently characterized. Here, we describe a method for purifying organelle membranes from yeast, MemPrep. We demonstrate the purity of our ER membrane preparations by proteomics, and document the general utility of MemPrep by isolating vacuolar membranes. Quantitative lipidomics establishes the lipid composition of the ER and the vacuolar membrane. Our findings provide a baseline for studying membrane protein biogenesis and have important implications for understanding the role of lipids in regulating the unfolded protein response (UPR). The combined preparative and analytical MemPrep approach uncovers dynamic remodeling of ER membranes in stressed cells and establishes distinct molecular fingerprints of lipid bilayer stress.
    Keywords:  ER Stress; Lipid Bilayer Stress; MemPrep; Organelle Lipidomics; UPR
    DOI:  https://doi.org/10.1038/s44318-024-00063-y
  13. J Clin Invest. 2024 Mar 21. pii: e166795. [Epub ahead of print]
    Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment.
    Xu Li, Tongzhou Liang, Bingyang Dai, Liang Chang, Yuan Zhang, Shiwen Hu, Jiaxin Guo, Shunxiang Xu, Lizhen Zheng, Hao Yao, Hong Lian, Yu Nie, Ye Li, Xuan He, Zhi Yao, Wenxue Tong, Xinluan Wang, Dick Ho Kiu Chow, Jiankun Xu, Ling Qin.
      Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remains unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status, notably, obstructed fatty acid transportation, was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of Bmp2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.
    Keywords:  Bone biology; Bone disease; Fatty acid oxidation; Osteoporosis
    DOI:  https://doi.org/10.1172/JCI166795
  14. J Exp Med. 2024 Apr 01. pii: e20231263. [Epub ahead of print]221(4):
    ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype.
    Naveen Sharma, Xiaozhou Fan, Oluwatomisin T Atolagbe, Zhongqi Ge, Kelly N Dao, Padmanee Sharma, James P Allison.
      We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1. Macrophage depletion with clodronate reduced the tumor-infiltrating effector CD4 and CD8 T cells, impairing their antitumor functions. Furthermore, the recruitment and polarization of M1-like macrophages required IFN-γ. Therefore, in this study, we show that there is a positive feedback loop between intratumoral effector T cells and tumor-associated macrophages (TAMs), in which the IFN-γ produced by the T cells polarizes the TAMs into M1-like phenotype, and the TAMs, in turn, reshape the tumor microenvironment to facilitate T cell infiltration, immune function, and tumor rejection.
    DOI:  https://doi.org/10.1084/jem.20231263
  15. Redox Biol. 2024 Mar 14. pii: S2213-2317(24)00096-X. [Epub ahead of print]71 103120
    Visualizing mitochondrial heme flow through GAPDH in living cells and its regulation by NO.
    Pranjal Biswas, Joseph Palazzo, Simon Schlanger, Dhanya Thamaraparambil Jayaram, Sidra Islam, Richard C Page, Dennis J Stuehr.
      Iron protoporphyrin IX (heme) is a redox-active cofactor that is bound in mammalian cells by GAPDH and allocated by a process influenced by physiologic levels of NO. This impacts the activity of many heme proteins including indoleamine dioxygenase-1 (IDO1), a redox enzyme involved in immune response and tumor growth. To gain further understanding we created a tetra-Cys human GAPDH reporter construct (TC-hGAPDH) which after labeling could indicate its heme binding by fluorescence quenching. When purified or expressed in a human cell line, TC-hGAPDH had properties like native GAPDH and heme binding quenched its fluorescence by 45-65%, allowing it to report on GAPDH binding of mitochondrially-generated heme in live cells in real time. In cells with active mitochondrial heme synthesis, low-level NO exposure increased heme allocation to IDO1 while keeping the TC-hGAPDH heme level constant due to replenishment by mitochondria. When mitochondrial heme synthesis was blocked, low NO caused a near complete transfer of the existing heme in TC-hGAPDH to IDO1 in a process that required IDO1 be able to bind the heme and have an active hsp90 present. Higher NO exposure had the opposite effect and caused IDO1 heme to transfer back to TC-hGAPDH. This demonstrated: (i) flow of mitochondrial heme through GAPDH is tightly coupled to target delivery, (ii) NO up- or down-regulates IDO1 activity by promoting a conserved heme exchange with GAPDH that goes in either direction according to the NO exposure level. The ability to drive a concentration-dependent, reversible protein heme exchange is unprecedented and reveals a new role for NO in biology.
    Keywords:  GAPDH; Heme protein; Heme trafficking; Hsp90; IDO1; Mitochondria
    DOI:  https://doi.org/10.1016/j.redox.2024.103120
  16. Cell Rep Med. 2024 Mar 19. pii: S2666-3791(24)00123-X. [Epub ahead of print]5(3): 101477
    Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.
    Weize Zhu, Ying Hong, Zhaowei Tong, Xiaofang He, Yan Li, Hao Wang, Xinxin Gao, Pengtao Song, Xianshan Zhang, Xiaochang Wu, Zhenhua Tan, Wenjin Huang, Zekun Liu, Yiyang Bao, Junli Ma, Ningning Zheng, Cen Xie, Xisong Ke, Wen Zhou, Wei Jia, Mingxiao Li, Jing Zhong, Lili Sheng, Houkai Li.
      Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.
    Keywords:  MASH; SCAP-SREBPs pathway; adenosine A1 receptor; de novo lipogenesis; inflammation
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101477
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