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Experimental & Molecular Medicine Mar 2022It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes... (Review)
Review
It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response.
Topics: Cell Differentiation; Humans; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Sirtuins; T-Lymphocytes
PubMed: 35296782
DOI: 10.1038/s12276-022-00739-7 -
The Journal of Biological Chemistry 2021Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates... (Review)
Review
Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates metabolic processes may provide new opportunities to prevent and treat these epidemics. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a sugar-sensing transcription factor that mediates genomic responses to changes in carbohydrate abundance in key metabolic tissues. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-alpha, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-beta. Carbohydrate metabolites and other metabolic signals may also regulate ChREBP activity via posttranslational modifications including phosphorylation, acetylation, and O-GlcNAcylation that can affect ChREBP's cellular localization, stability, binding to cofactors, and transcriptional activity. In this review, we discuss mechanisms regulating ChREBP activity and highlight phenotypes and controversies in ChREBP gain- and loss-of-function genetic rodent models focused on the liver and pancreatic islets.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carbohydrate Metabolism; Glucose; Hexoses; Homeostasis; Humans; Islets of Langerhans; Lipid Metabolism; Liver; Mutation; Protein Processing, Post-Translational; Rodentia
PubMed: 33812993
DOI: 10.1016/j.jbc.2021.100623 -
Accounts of Chemical Research Nov 2022Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological... (Review)
Review
Signaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.
Topics: Animals; Mice; Endocannabinoids; Lipid Metabolism; Brain; Neurons; Synaptic Transmission
PubMed: 36283077
DOI: 10.1021/acs.accounts.2c00521 -
Current Obesity Reports Jun 2020There is substantial inter-individual variability in body weight change, which is not fully accounted by differences in daily energy intake and physical activity levels.... (Review)
Review
PURPOSE OF REVIEW
There is substantial inter-individual variability in body weight change, which is not fully accounted by differences in daily energy intake and physical activity levels. The metabolic responses to short-term perturbations in energy intake can explain part of this variability by quantifying the degree of metabolic "thriftiness" that confers more susceptibility to weight gain and more resistance to weight loss. It is unclear which metabolic factors and pathways determine this human "thrifty" phenotype. This review will investigate and summarize emerging research in the field of energy metabolism and highlight important metabolic mechanisms implicated in body weight regulation in humans.
RECENT FINDINGS
Dysfunctional adipose tissue lipolysis, reduced brown adipose tissue activity, blunted fibroblast growth factor 21 secretion in response to low-protein hypercaloric diets, and impaired sympathetic nervous system activity might constitute important metabolic factors characterizing "thriftiness" and favoring weight gain in humans. The individual propensity to weight gain in the current obesogenic environment could be ascertained by measuring specific metabolic factors which might open up new pathways to prevent and treat human obesity.
Topics: Adipose Tissue; Body Weight; Diet, Protein-Restricted; Energy Metabolism; Fasting; Fibroblast Growth Factors; Ghrelin; Humans; Lipolysis; Liver; Obesity; Sympathetic Nervous System; Weight Gain; Weight Loss
PubMed: 32248352
DOI: 10.1007/s13679-020-00371-4 -
Cell Proliferation Nov 2020Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation.... (Review)
Review
Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation. Although nutrient availability strongly impacts the process of autophagy, the specific metabolites that regulate autophagic responses have not yet been determined. Recent results indicate that S-adenosylmethionine (SAM) represents a critical inhibitor of methionine starvation-induced autophagy. SAM is primarily involved in four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5'-deoxyadenosyl 5'-radical-mediated biochemical transformations. SAM is the sole methyl group donor involved in the methylation of DNA, RNA and histones, modulating the autophagic process by mediating epigenetic effects. Moreover, the metabolites of SAM, such as homocysteine, glutathione, decarboxylated SAM and spermidine, also exert important influences on the regulation of autophagy. From our perspective, nuclear-cytosolic SAM is a conserved metabolic inhibitor that connects cellular metabolic status and the regulation of autophagy. In the future, SAM might be a new target of autophagy regulators and be widely used in the treatment of various diseases.
Topics: Animals; Autophagy; DNA Methylation; Epigenesis, Genetic; Humans; Metabolic Networks and Pathways; S-Adenosylmethionine
PubMed: 33030764
DOI: 10.1111/cpr.12891 -
Journal of Hematology & Oncology Aug 2022Metabolic reprogramming of cancer cells within the tumor microenvironment typically occurs in response to increased nutritional, translation and proliferative demands.... (Review)
Review
Metabolic reprogramming of cancer cells within the tumor microenvironment typically occurs in response to increased nutritional, translation and proliferative demands. Altered lipid metabolism is a marker of tumor progression that is frequently observed in aggressive tumors with poor prognosis. Underlying these abnormal metabolic behaviors are posttranslational modifications (PTMs) of lipid metabolism-related enzymes and other factors that can impact their activity and/or subcellular localization. This review focuses on the roles of these PTMs and specifically on how they permit the re-wiring of cancer lipid metabolism, particularly within the context of the tumor microenvironment.
Topics: Humans; Lipid Metabolism; Lipogenesis; Neoplasms; Protein Processing, Post-Translational; Tumor Microenvironment
PubMed: 36038892
DOI: 10.1186/s13045-022-01340-1 -
Frontiers in Immunology 2019Class 1 Phosphoinositide-3-Kinases (PI3Ks) have been widely studied and mediate essential roles in cellular proliferation, chemotaxis, insulin sensitivity, and immunity.... (Review)
Review
Class 1 Phosphoinositide-3-Kinases (PI3Ks) have been widely studied and mediate essential roles in cellular proliferation, chemotaxis, insulin sensitivity, and immunity. Here, we provide a comprehensive overview of how macrophage expressed PI3Ks and their downstream pathways orchestrate responses to metabolic stimuli and nutrients, polarizing macrophages, shaping their cellular identity and function. Particular emphasis will be given to adipose tissue macrophages, crucial players of insulin resistance and chronic metabolically triggered inflammation during obesity. An understanding of PI3K dependent wiring of macrophage responses is important as this is involved in various diseases ranging from obesity, type 2 diabetes to chronic inflammatory disease.
Topics: Adipose Tissue; Animals; Cell Survival; Glucose; Humans; Insulin; Lipid Metabolism; Macrophage Activation; Macrophages; Myeloid Cells; Obesity; Phosphatidylinositol 3-Kinases
PubMed: 31497027
DOI: 10.3389/fimmu.2019.02002 -
Toxins Sep 2020is a metabolically flexible pathogen that causes infection in diverse settings. An array of virulence factors, including the secreted toxins, enables to colonize... (Review)
Review
is a metabolically flexible pathogen that causes infection in diverse settings. An array of virulence factors, including the secreted toxins, enables to colonize different environmental niches and initiate infections by any of several discrete pathways. During these infections, both and host cells compete with each other for nutrients and remodel their metabolism for survival. This metabolic interaction/crosstalk determines the outcome of the infection. The reprogramming of metabolic pathways in host immune cells not only generates adenosine triphosphate (ATP) to meet the cellular energy requirements during the infection process but also activates antimicrobial responses for eventual bacterial clearance, including cell death pathways. The selective pressure exerted by host immune cells leads to the emergence of bacterial mutants adapted for chronicity. These host-adapted mutants are often characterized by substantial changes in the expression of their own metabolic genes, or by mutations in genes involved in metabolism and biofilm formation. Host-adapted can rewire or benefit from the metabolic activities of the immune cells via several mechanisms to cause persistent infection. In this review, we discuss how activates host innate immune signaling, which results in an immune metabolic pressure that shapes metabolic adaptation and determines the outcome of the infection.
Topics: Animals; Energy Metabolism; Host-Pathogen Interactions; Humans; Immunity, Innate; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Virulence; Virulence Factors
PubMed: 32917040
DOI: 10.3390/toxins12090581 -
Cell Reports Jun 2023Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation...
Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.
Topics: Tyrosine-tRNA Ligase; Protein Transport; Phosphorylation; Nuclear Localization Signals; Oxidative Stress
PubMed: 37314928
DOI: 10.1016/j.celrep.2023.112632 -
Nature Communications Mar 2023Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem....
Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem. Especially for microbes, which are metabolically diverse and often interact in complex communities, few phenotypes can be determined directly. Instead, potential phenotypes are commonly inferred from genomic information, and rarely were model-predicted phenotypes employed beyond the species level. Here, we propose sensitivity correlations to quantify similarity of predicted metabolic network responses to perturbations, and thereby link genotype and environment to phenotype. We show that these correlations provide a consistent functional complement to genomic information by capturing how network context shapes gene function. This enables, for example, phylogenetic inference across all domains of life at the organism level. For 245 bacterial species, we identify conserved and variable metabolic functions, elucidate the quantitative impact of evolutionary history and ecological niche on these functions, and generate hypotheses on associated metabolic phenotypes. We expect our framework for the joint interpretation of metabolic phenotypes, evolution, and environment to help guide future empirical studies.
Topics: Phylogeny; Phenotype; Genotype; Metabolic Networks and Pathways; Genomics; Gene Regulatory Networks
PubMed: 36973280
DOI: 10.1038/s41467-023-37429-5