bims-mepmim 2024-10-27 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–10–27
twenty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Glutamine sensing licenses cholesterol synthesis.
Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.
Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.
2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion.
Mitochondrial fatty acid oxidation drives senescence.
The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.
The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
Cyclophilin D plays a critical role in the survival of senescent cells.
Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice.
Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.
A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy.
The hepcidin-ferroportin axis modulates liver endothelial cell BMP expression to influence iron homeostasis in mice.
METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.
CD36-mediated arachidonic acid influx from decidual stromal cells increases inflammatory macrophages in miscarriage.
Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression.
Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer.
Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits.
Targeting immune-fibroblast cell communication in heart failure.

EMBO J. 2024 Oct 21.

Glutamine sensing licenses cholesterol synthesis.

Bruna Martins Garcia, Philipp Melchinger, Tania Medeiros, Sebastian Hendrix, Kavan Prabhu, Mauro Corrado, Jenina Kingma, Andrej Gorbatenko, Soni Deshwal, Matteo Veronese, Luca Scorrano, Erika Pearce, Patrick Giavalisco, Noam Zelcer, Lena Pernas.

  The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.

Keywords:  Cholesterol; HMGCR; MFN2; Nutrient Sensing; SREBP2

DOI:  https://doi.org/10.1038/s44318-024-00269-0
Cell Chem Biol. 2024 Oct 14. pii: S2451-9456(24)00404-5. [Epub ahead of print]

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Kelly H Sokol, Cameron J Lee, Thomas J Rogers, Althea Waldhart, Abigail E Ellis, Sahithi Madireddy, Samuel R Daniels, Rachel Rae J House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R Furness, Ryan D Sheldon, Evan C Lien.

  Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Keywords:  cancer; ferroptosis; lipid metabolism; phospholipids; polyunsaturated fatty acids; triglycerides

DOI:  https://doi.org/10.1016/j.chembiol.2024.09.008
Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00328-X. [Epub ahead of print]

Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.

Rosana-Bristena Ionescu, Alexandra M Nicaise, Julie A Reisz, Eleanor C Williams, Pranathi Prasad, Cory M Willis, Madalena B C Simões-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D'Alessandro, Stefano Pluchino.

  Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.

Keywords:  cellular senescence; cholesterol metabolism; disease modeling; lipid droplets; multi-omics; multiple sclerosis; neural stem cells; neuroimmunology; neurotoxicity; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.stem.2024.09.014
J Biol Chem. 2024 Oct 21. pii: S0021-9258(24)02414-1. [Epub ahead of print] 107912

2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion.

Hong Li, Lin Lin, Xiaoheng Huang, Yang Lu, Xiong Su.

  Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D.

Keywords:  Diabetes; FA2H; Fatty acid; Fatty acid 2-hydroxylation; GLUT2; Glucose transport; Insulin secretion; Metabolism; β-cells

DOI:  https://doi.org/10.1016/j.jbc.2024.107912
Sci Adv. 2024 Oct 25. 10(43): eado5887

Mitochondrial fatty acid oxidation drives senescence.

Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.

Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.

DOI: https://doi.org/10.1126/sciadv.ado5887
Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2318767121

The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.

Eri Oguro-Igashira, Mari Murakami, Ryota Mori, Ryuichi Kuwahara, Takako Kihara, Masaharu Kohara, Makoto Fujiwara, Daisuke Motooka, Daisuke Okuzaki, Mitsuru Arase, Hironobu Toyota, Siyun Peng, Takayuki Ogino, Yasuji Kitabatake, Eiichi Morii, Seiichi Hirota, Hiroki Ikeuchi, Eiji Umemoto, Atsushi Kumanogoh, Kiyoshi Takeda.

  The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues.

Keywords:  G protein-coupled receptors; GPR31; antigen recognition; dendritic cell; transepithelial dendrite formation

DOI:  https://doi.org/10.1073/pnas.2318767121
Mucosal Immunol. 2024 Oct 18. pii: S1933-0219(24)00105-3. [Epub ahead of print]

Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.

Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne.

The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.

DOI: https://doi.org/10.1016/j.mucimm.2024.10.002
Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2401218121

The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.

Yumei Yang, Baomin Wang, Haoru Dong, Huige Lin, Melody Yuen-Man Ho, Ke Hu, Na Zhang, Jing Ma, Rong Xie, Kenneth King-Yip Cheng, Xiaomu Li.

  Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.

Keywords:  MDM2; cellular senescence; diabetes; p53; pyruvate carboxylase

DOI:  https://doi.org/10.1073/pnas.2401218121
EMBO J. 2024 Oct 24.

Cyclophilin D plays a critical role in the survival of senescent cells.

Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.

  Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering

DOI:  https://doi.org/10.1038/s44318-024-00259-2
Sci Adv. 2024 Oct 25. 10(43): eado9311

Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice.

Xiaoju Shi, Qianqian Zheng, Xingtong Wang, Wei Guo, Ziqi Lin, Yonglin Gao, Emily Shore, Robert C Martin, Guoyue Lv, Yan Li.

Metabolic dysfunction-associated steatohepatitis is well accepted as a potential precursor of hepatocellular carcinoma. Previously, we reported that fibroblast growth factor 21 (FGF21) revealed a novel anti-inflammatory activity via inhibiting the TLR4-IL-17A signaling, which could be a potential anticarcinogenetic mechanism to prevent to MASH-HCC transition. Here, we set out to determine whether FGF21 has a major impact on Kupffer cells' (KCs) ability during MASH-HCC transition. We found aberrant hepatic FGF21 and KC pool in human MASH-HCC. Lack of FGF21 up-regulated ALOX15, which converted the oxidized fatty acids to induce excessive KC death and mobilization of monocyte-derived macrophages (MoMFs) for KC replacement. Lack of FGF21 oversupplied free fatty acids for sphingosine-1-phosphate (S1P) cascade synthesis to mediate MASH-HCC transition via S1P-YAP signaling and cross-talk between tumor cells and macrophages. In conclusion, lack of FGF21 accelerated MASH-HCC transition via the S1P-AP signaling. Compromised MoMFs could present as tumor-associated macrophage phenotype rendering tumor immune microenvironment for MASH-HCC transition.

DOI: https://doi.org/10.1126/sciadv.ado9311
Sci Rep. 2024 10 21. 14(1): 24674

Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.

Maria Rosaria Ambrosio, Michiel Adriaens, Kasper Derks, Teresa Migliaccio, Valerio Costa, Domenico Liguoro, Simona Cataldi, Vittoria D'Esposito, Giovanni Maneli, Rita Bassolino, Simone Di Paola, Marinella Pirozzi, Fabrizio Schonauer, Francesco D'Andrea, Francesco Beguinot, Ilja Arts, Pietro Formisano.

  An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. To explore BC-adipocytes interaction and define the impact of glucose in such dialogue, Mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER+ BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). The transcriptome of both cell types in co-culture as in mono-culture was profiled by RNA-Seq to define the impact of adipocytes on BC cells and viceversa (i), the action of glucose on BC cells, adipocytes (ii) and their crosstalk (iii). Noteworthy, we provided evidence that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, our data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients.

Keywords:  Adipogenesis; Breast Cancer; Glucose; Mammary Adipocytes; Transcriptional signatures; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s41598-024-76522-7
Cell. 2024 Oct 19. pii: S0092-8674(24)00903-6. [Epub ahead of print]

A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.

Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang.

  The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.

Keywords:  adaptation; breakfast skipping; in vivo metabolite tracing; metabolic heterogeneity; multi-omics; the small intestine; two-front nutrient supply; zonated function of enterocyte

DOI:  https://doi.org/10.1016/j.cell.2024.08.012
Nat Commun. 2024 Oct 21. 15(1): 9062

Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy.

Zachary Dewald, Oluwafolajimi Adesanya, Haneui Bae, Andrew Gupta, Jessica M Derham, Ullas V Chembazhi, Auinash Kalsotra.

Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.

DOI: https://doi.org/10.1038/s41467-024-53378-z
Blood. 2024 Oct 22. pii: blood.2024024795. [Epub ahead of print]

The hepcidin-ferroportin axis modulates liver endothelial cell BMP expression to influence iron homeostasis in mice.

Allison L Fisher, Sydney Phillips, Chia-Yu Wang, Joao A Paulo, Xia Xiao, Yang Xu, Gillian A Moschetta, Yongqiang Xue, Joseph D Mancias, Jodie L Babitt.

The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs), which activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and thereby hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression as control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.

DOI: https://doi.org/10.1182/blood.2024024795
Nat Commun. 2024 Oct 22. 15(1): 9110

METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.

Bishoy Wadie, Lachlan Stuart, Christopher M Rath, Bernhard Drotleff, Sergii Mamedov, Theodore Alexandrov.

Imaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.

DOI: https://doi.org/10.1038/s41467-024-52213-9
EMBO Mol Med. 2024 Oct 21.

Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.

Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito.

  The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

Keywords:  Breast Cancer; Ferroptosis; Lipid Metabolism; Metastasis; Selenium Metabolism

DOI:  https://doi.org/10.1038/s44321-024-00142-x
Cell Rep. 2024 Oct 19. pii: S2211-1247(24)01232-4. [Epub ahead of print]43(11): 114881

CD36-mediated arachidonic acid influx from decidual stromal cells increases inflammatory macrophages in miscarriage.

Jiajia Chen, Tingxuan Yin, Xianyang Hu, Lingyu Chang, Yifei Sang, Ling Xu, Weijie Zhao, Lu Liu, Chunfang Xu, Yikong Lin, Yue Li, Qingyu Wu, Dajin Li, Yanhong Li, Meirong Du.

  Spontaneous abortion is associated with aberrant lipid metabolism, but the underlying mechanisms remain unclear. Here, we show that lipids are accumulated in decidual stromal cells (DSCs) and macrophages (dMφs) in women with miscarriage and mouse abortion-prone models. Moreover, we show that excessive lipids from DSCs are transferred to dMφs via a CD36-dependent mechanism that induces inflammation in dMφs. In particular, DSC-derived arachidonic acid (AA) is internalized by dMφs via CD36, which activates cyclooxygenase 2-dependent prostaglandin E2 production and interleukin (IL)-1β expression. In mice, AA injection induces miscarriage, whereas conditional knockout of Cd36 in dMφs ameliorates AA-induced embryo loss. Additionally, DSC-derived prolactin (PRL) inhibits CD36-mediated lipid intake in dMφs, and PRL administration reduces embryo loss in pregnant mice treated with CD36+ Mφs. Our findings reveal a critical interplay between DSCs and dMφs in dysregulated lipid metabolism that may contribute to miscarriage, in which PRL may be harnessed as a therapeutic agent.

Keywords:  CP: Developmental biology; CP: Immunology

DOI:  https://doi.org/10.1016/j.celrep.2024.114881
Cell Death Dis. 2024 Oct 23. 15(10): 770

Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression.

Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li.

Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2HKO) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.

DOI: https://doi.org/10.1038/s41419-024-07151-1
J Clin Invest. 2024 Oct 22. pii: e180282. [Epub ahead of print]

Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer.

Ru M Wen, Jessica C Stark, G Edward W Marti, Zenghua Fan, Aram Lyu, Fernando Jose Garcia Marques, Xiangyue Zhang, Nicholas M Riley, Sarah M Totten, Abel Bermudez, Rosalie Nolley, Hongjuan Zhao, Lawrence Fong, Edgar G Engleman, Sharon J Pitteri, Carolyn R Bertozzi, James D Brooks.

  Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor-based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid-binding immunoglobulin-like lectins) are expressed on immune cells and regulate immune responses and function. Siglec-7 and Siglec-9 contribute to immune evasion by interacting with their ligands. However, the role of Siglec-7/9 receptors and their ligands in prostate cancer remains poorly understood. Here, we find that Siglec-7 and Siglec-9 are associated with poor prognosis in prostate cancer patients, and are highly expressed in myeloid cells, including macrophages, in prostate tumor tissues. Siglecs-7 and -9 ligands were expressed in prostate cancer cells and human prostate tumor tissues. Blocking the interactions between Siglec-7/9 and sialic acids inhibited prostate cancer xenograft growth and increased immune cell infiltration in humanized mice in vivo. Using a CRISPRi screen and mass spectrometry, we identified CD59 as a candidate Siglec-9 ligand in prostate cancer. The identification of Siglecs-7 and -9 as potential therapeutic targets, including CD59/Siglec-9 axis, opens up opportunities for immune-based interventions in prostate cancer.

Keywords:  Cancer immunotherapy; Immunotherapy; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI180282
J Clin Invest. 2024 Oct 22. pii: e182325. [Epub ahead of print]

Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits.

Antwi-Boasiako Oteng, Liu Liu, Yinghong Cui, Oksana Gavrilova, Huiyan Lu, Min Chen, Lee S Weinstein, Jonathan E Campbell, Jo E Lewis, Fiona M Gribble, Frank Reimann, Jürgen Wess.

  Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.

Keywords:  Diabetes; Endocrinology; G proteincoupled receptors; G proteins

DOI:  https://doi.org/10.1172/JCI182325
Nature. 2024 Oct 23.

Targeting immune-fibroblast cell communication in heart failure.

Junedh M Amrute, Xin Luo, Vinay Penna, Steven Yang, Tracy Yamawaki, Sikander Hayat, Andrea Bredemeyer, In-Hyuk Jung, Farid F Kadyrov, Gyu Seong Heo, Rajiu Venkatesan, Sally Yu Shi, Alekhya Parvathaneni, Andrew L Koenig, Christoph Kuppe, Candice Baker, Hannah Luehmann, Cameran Jones, Benjamin Kopecky, Xue Zeng, Tore Bleckwehl, Pan Ma, Paul Lee, Yuriko Terada, Angela Fu, Milena Furtado, Daniel Kreisel, Atilla Kovacs, Nathan O Stitziel, Simon Jackson, Chi-Ming Li, Yongjian Liu, Nadia A Rosenthal, Rafael Kramann, Brandon Ason, Kory J Lavine.

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction1,2. However, the molecular mechanisms driving immune-fibroblast cell communication in human cardiac disease remain unexplored and there are at present no approved treatments that directly target cardiac fibrosis3,4. Here we performed multiomic single-cell gene expression, epitope mapping and chromatin accessibility profiling in 45 healthy donor, acutely infarcted and chronically failing human hearts. We identified a disease-associated fibroblast trajectory that diverged into distinct populations reminiscent of myofibroblasts and matrifibrocytes, the latter expressing fibroblast activator protein (FAP) and periostin (POSTN). Genetic lineage tracing of FAP+ fibroblasts in vivo showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model cardiac fibroblasts and demonstrated that three different in vivo mouse models of cardiac injury were superior compared with cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin-1β (IL-1β) signalling drove the emergence of FAP/POSTN fibroblasts within spatially defined niches. In vivo, we deleted the IL-1 receptor on fibroblasts and the IL-1β ligand in CCR2+ monocytes and macrophages, and inhibited IL-1β signalling using a monoclonal antibody, and showed reduced FAP/POSTN fibroblasts, diminished myocardial fibrosis and improved cardiac function. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.

DOI: https://doi.org/10.1038/s41586-024-08008-5