scholarly journals Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis

2017 ◽  
Vol 313 (5) ◽  
pp. L834-L844 ◽  
Author(s):  
Na Xie ◽  
Huachun Cui ◽  
Jing Ge ◽  
Sami Banerjee ◽  
Sijia Guo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Pulmonary Fibrosis ◽  
Fatty Acid Oxidation ◽  
Expression Profile ◽  
Alveolar Macrophages ◽  
Lung Fibrosis ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Rna Profiling ◽  
Enhanced Expression

Metabolic reprogramming has been intrinsically linked to macrophage activation. Alveolar macrophages are known to play an important role in the pathogenesis of pulmonary fibrosis. However, systematic characterization of expression profile in these cells is still lacking. Furthermore, main metabolic programs and their regulation of cellular phenotype are completely unknown. In this study, we comprehensively analyzed the expression profile and main metabolic programs in alveolar macrophages from mice with or without experimental pulmonary fibrosis. We found that alveolar macrophages from both bleomycin and active TGF-β1-induced fibrotic mouse lungs demonstrated a primarily profibrotic M2-like profile that was distinct from the well-defined M1 or any of the M2 subtypes. More importantly, we found that fibrotic lung alveolar macrophages assumed augmented glycolysis, which was likely attributed to enhanced expression of multiple key glycolytic mediators. We also found that fatty acid oxidation was upregulated in these cells. However, the profibrotic M2-like profile of fibrotic lung alveolar macrophages was not dependent on fatty acid oxidation and synthesis or lipolysis, but instead on glycolysis, in contrast to the typical IL-4-induced macrophages M(IL-4). Additionally, glutaminolysis, a key metabolic program that has been implicated in numerous pathologies, was not required for the profibrotic M2-like phenotype of these macrophages. In summary, our study identifies a unique expression and metabolic profile in alveolar macrophages from fibrotic lungs and suggests glycolytic inhibition as an effective antifibrotic strategy in treating lung fibrosis.

High PRMT1 Expression Promotes the Progression of Acute Megakaryocytic Leukemia Via Controlling Metabolic Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1551-1551
Author(s):  
Hairui Su ◽  
Han Guo ◽  
Ngoc-Tung Tran ◽  
Minkui Luo ◽  
Xinyang Zhao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Pathways ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Epigenetic Changes ◽  
Acute Megakaryocytic Leukemia ◽  
Megakaryocyte Differentiation

Abstract Metabolic reprogramming is needed not only to accommodate but also to drive leukemia progression. Yet very little is known on genetic factors other than IDH1 mutations, which can drive leukemogenesis via metabolic reprogramming. Here, we will present data to suggest that protein arginine methyltransferases 1 (PRMT1) is a driver for acute megakaryocytic leukemia via reprogramming metabolism. PRMT1 is highly expressed in megakaryocyte-erythrocyte progenitor cells and downregulated during the terminal differentiation of megakaryocytes. Constitutively high expression of PRMT1 in acute megakaryoblastic leukemia (AMKL) blocks megakaryocyte differentiation. PRMT1 upregulates RBM15 protein level via methylation-dependent ubiquitylation pathway (Zheng et al. Elife, 2015). In this presentation, we discovered that metabolic stress such as hypoxia downregulates PRMT1 protein level. Thus, metabolic stress is the upstream signal for the PRMT1-RBM15 pathway. We have identified that RBM15 specifically binds to 3'UTR of mRNAs of genes involved in metabolic pathways. Using RNA-immunoprecipitation with anti-RBM15 antibody and real-time PCR assays, we validated that RBM15 binds to mRNAs of genes involved in fatty acid oxidation and glycolysis. We transduced PRMT1 into an RBM15-MKL1 expressing cell line 6133. Overexpression of PRMT1 renders 6133 cells to grow in a cytokine-independent manner with increased mitochondria biogenesis, which in turn produces higher concentration of ATP in our metabolomic analysis. Based on the analysis of metabolomics data and RBM15-target genes, we conclude that PRMT1 promotes the usage of glucose as bioenergy via oxidative phosphorylation and inhibits fatty acid oxidation. Given that acetyl-coA is higher in PRMT1 expressing 6133 cells, we asked whether histone acetylation is upregulated in PRMT1 overexpressed 6133 cells. Indeed, we found higher histone acetylation level in PRMT1 highly expressed cells. We also found that propionylated histone is reduced, which is consistent with reduced fatty acid oxidation. Propionyl-CoA molecules are produced from fatty acids with odd carbon numbers. Thus PRMT1-mediated metabolic reprogramming changes epigenetic programming during leukemia progression. Intriguing, we also found PRMT1 overexpression enhances histone H3S10 phosphorylation via methylation-dependent ubiquitylation of DUSP4. DUSP4 promotes polyploidy during megakaryocyte differentiation. Thus PRMT1 caused profound epigenetic changes to promote leukemogenesis. In this vein, we established mouse AMKL models by bone marrow transplantation of 6133 cells as well as human AMKL patient samples respectively. Using this mouse model, we tested PRMT1 inhibitors, acetyltransferase inhibitors as well as other metabolic inhibitors. Treating cells with PRMT1 inhibitors as well as metabolic inhibitors promote MK differentiation of AMKL leukemia cells. Metabolomics analysis of cells recovered from mouse models will be discussed in the presentation. In summary, our data demonstrated that PRMT1 is a major sensor for metabolic stress and that PRMT1 in turn reprograms metabolic pathways to bring epigenetic changes in leukemogenesis. Therefore, targeting PRMT1 and downstream PRMT1-regulated metabolic pathways will offer new avenues in treating acute megakaryocytic leukemia and other hematological malignancies with defective megakaryocyte differentiation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of Fatty Acid Oxidation and Its Regulation on Dendritic Cell-Mediated Immune Responses in Allergies: An Immunometabolism Perspective

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Shanfeng Sun ◽  
Yanjun Gu ◽  
Junjuan Wang ◽  
Cheng Chen ◽  
Shiwen Han ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fatty Acid ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Fatty Acid Oxidation ◽  
Cell Activation ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Dendritic Cell Activation ◽  
Functional Changes

Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.

Role of metabolic reprogramming toward fatty acid oxidation on tumor lymph node metastasis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Choong-kun Lee ◽  
Seung-hwan Jeong ◽  
Cholsoon Jang ◽  
Hosung Bae ◽  
Yoo Hyung Kim ◽  
...  
Keyword(s):  
Lymph Node ◽  
Fatty Acid ◽  
Tumor Cells ◽  
Fatty Acid Oxidation ◽  
Strong Predictor ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metastatic Tumors ◽  
Genetic Ablation

e14501 Background: Metastasis of tumors to lymph node (LN) is a strong predictor of cancer patient mortality and determinant of disease progression and treatment options. Despite the clinical significance of tumor LN metastasis, the mechanisms underlying this process remain largely unexplored. Methods: We used comparative transcriptomics and metabolomics analyses of the primary tumor and LN micro- and macro-metastatic tumors from B16F10 murine melanoma model. B16F10 melanoma footpad implantation model and MMTV-PyMT spontaneous breast cancer genetic mouse models were analyzed in vivo. We also investigated the LN-metastatic tumors from sentinel LNs in 21 patients with melanoma. Results: We found that tumor cells undergo dramatic metabolic reprogramming towards fatty acid oxidation (FAO) for successful LN metastasis. Mechanistically, transcription co-activator YAP is selectively activated in LN metastatic tumors, leading to stimulation of FAO gene programs. Pharmacological inhibition of FAO or genetic ablation of YAP in tumors markedly suppressed LN metastasis. Unexpectedly, metastatic tumors highly stimulated the bile acid synthesis pathway upon arrival at the LN, and these bile acids activated YAP of tumor cells via nuclear vitamin D receptor. Lastly, YAP activation in the metastatic LNs of melanoma patients was reversely correlated with distant metastasis–free survival. Conclusions: This study propose that inhibition of FAO or YAP signaling to prevent the metabolic reprogramming of metastatic tumors offers a potential therapeutic strategy for mitigating tumor LN metastasis.

scholarly journals Metabolic re-patterning in COPD airway smooth muscle cells

2017 ◽  
Vol 50 (5) ◽  
pp. 1700202 ◽  
Author(s):  
Charalambos Michaeloudes ◽  
Chih-Hsi Kuo ◽  
Gulam Haji ◽  
Donna K. Finch ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Airway Smooth Muscle ◽  
Redox Balance ◽  
Growth Conditions ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Oxidation Capacity

Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.

scholarly journals Glycolytic and lipid oxidative metabolic programs are essential for freshly-isolated regulatory T cells in mice with sepsis

RSC Advances ◽  
2020 ◽  
Vol 10 (35) ◽  
pp. 21000-21008
Author(s):  
Xiaomei Zhu ◽  
WenQing Ji ◽  
Shubin Guo ◽  
Di Zhu ◽  
Yue Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Regulatory T Cells ◽  
Fatty Acid Oxidation ◽  
Treg Cells ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

Freshly-isolated Treg cells showed metabolic reprogramming in mice with sepsis, mainly manifested by increased glycolysis and fatty acid oxidation pathways.

Metabolic Remodeling Induced by Adipocytes: A New Achilles' Heel in Invasive Breast Cancer?

2020 ◽  
Vol 27 (24) ◽  
pp. 3984-4001 ◽  
Author(s):  
Camille Attané ◽  
Delphine Milhas ◽  
Andrew J. Hoy ◽  
Catherine Muller
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Fatty Acid Oxidation ◽  
De Novo ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Oxidation Inhibitors ◽  
Metabolic Remodeling

Metabolic reprogramming represents an important hallmark of cancer cells. Besides de novo fatty acid synthesis, it is now clear that cancer cells can acquire Fatty Acids (FA) from tumor-surrounding adipocytes to increase their invasive capacities. Indeed, adipocytes release FA in response to tumor secreted factors that are transferred to tumor cells to be either stored as triglycerides and other complex lipids or oxidized in mitochondria. Like all cells, FA can be released over time from triglyceride stores through lipolysis and then oxidized in mitochondria in cancer cells. This metabolic interaction results in specific metabolic remodeling in cancer cells, and underpins adipocyte stimulated tumor progression. Lipolysis and fatty acid oxidation therefore represent novel targets of interest in the treatment of cancer. In this review, we summarize the recent advances in our understanding of the metabolic reprogramming induced by adipocytes, with a focus on breast cancer. Then, we recapitulate recent reports studying the effect of lipolysis and fatty acid oxidation inhibitors on tumor cells and discuss the interest to target these metabolic pathways as new therapeutic approaches for cancer.

scholarly journals PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Nikolaos Patsoukis ◽  
Kankana Bardhan ◽  
Pranam Chatterjee ◽  
Duygu Sari ◽  
Bianling Liu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
T Cell ◽  
Fatty Acid Oxidation ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

scholarly journals Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation

2021 ◽  
Vol 118 (22) ◽  
pp. e2014681118
Author(s):  
Fengqi Hao ◽  
Miaomiao Tian ◽  
Xinbo Zhang ◽  
Xin Jin ◽  
Ying Jiang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Short Chain Fatty Acid ◽  
Chain Fatty Acid ◽  
Metabolic Reprogramming ◽  
Short Chain ◽  
Acid Oxidation ◽  
Immune Homeostasis ◽  
Metabolic Intermediate ◽  
Malonyl Coa

Inducible regulatory T (iTreg) cells play a crucial role in immune suppression and are important for the maintenance of immune homeostasis. Mounting evidence has demonstrated connections between iTreg differentiation and metabolic reprogramming, especially rewiring in fatty acid oxidation (FAO). Previous work showed that butyrate, a specific type of short-chain fatty acid (SCFA) readily produced from fiber-rich diets through microbial fermentation, was critical for the maintenance of intestinal homeostasis and capable of promoting iTreg generation by up-regulating histone acetylation for gene expression as an HDAC inhibitor. Here, we revealed that butyrate could also accelerate FAO to facilitate iTreg differentiation. Moreover, butyrate was converted, by acyl-CoA synthetase short-chain family member 2 (ACSS2), into butyryl-CoA (BCoA), which up-regulated CPT1A activity through antagonizing the association of malonyl-CoA (MCoA), the best known metabolic intermediate inhibiting CPT1A, to promote FAO and thereby iTreg differentiation. Mutation of CPT1A at Arg243, a reported amino acid required for MCoA association, impaired both MCoA and BCoA binding, indicating that Arg243 is probably the responsible site for MCoA and BCoA association. Furthermore, blocking BCoA formation by ACSS2 inhibitor compromised butyrate-mediated iTreg generation and mitigation of mouse colitis. Together, we unveil a previously unappreciated role for butyrate in iTreg differentiation and illustrate butyrate–BCoA–CPT1A axis for the regulation of immune homeostasis.

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