DOCSLIB.ORG

Carbohydrate and Amino Acid Metabolism As Hallmarks for Innate Immune Cell Activation and Function

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Carbohydrate and Amino Acid Metabolism As Hallmarks for Innate Immune Cell Activation and Function cells Review Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function 1, 1, 1,2, Haoxin Zhao y, Lydia N. Raines y and Stanley Ching-Cheng Huang * 1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; [email protected] (H.Z.); [email protected] (L.N.R.) 2 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA * Correspondence: [email protected]; Tel.: +1-216-368-3909 These authors have contributed equally. y Received: 10 February 2020; Accepted: 26 February 2020; Published: 27 February 2020 Abstract: Immune activation is now understood to be fundamentally linked to intrinsic and/or extrinsic metabolic processes which are essential for immune cells to survive, proliferate, and perform their effector functions. Moreover, disruption or dysregulation of these pathways can result in detrimental outcomes and underly a number of pathologies in both communicable and non-communicable diseases. In this review, we discuss how the metabolism of carbohydrates and amino acids in particular can modulate innate immunity and how perturbations in these pathways can result in failure of these immune cells to properly function or induce unfavorable phenotypes. Keywords: innate immunity; carbohydrates; amino acids; immunometabolism 1. Carbohydrate and Amino Acid Metabolism The field of immunometabolism has grown significantly over the past several decades, perhaps driven by the realization that cellular metabolism is fundamental to the activation and effector function of all cells within the body. While early links between immunity and metabolism were uncovered in the late 1900s, it was not until the early 2000s when it was observed that macrophages within the adipose tissue of obese mice exhibited an upregulation of inflammatory gene expression that this association was fully appreciated [1,2]. Since then, detailed reports into the activation and effector function of these adipose tissue-associated macrophages have paved the way to insights into how cellular metabolism affects other immune cell subtypes as well as how these signaling cascades influence global changes in these cells. Here, we discuss how carbohydrate and amino acid metabolism shape phenotypic outcomes in innate immune cells. 1.1. Carbohydrate Metabolism Perhaps the most well-known metabolic pathway is glycolysis. Glycolysis begins with the acquisition of glucose through glucose transporters (e.g., GLUT1) (Figure1). Upon entering the cell, glucose is catalytically broken down in the cytosol via an ATP-dependent hexokinase reaction into the first product of the glycolytic pathway glucose-6-phosphate (G6P). G6P is further metabolized to the eventual final glycolytic product pyruvate, resulting in a net gain of 2 ATP [3,4]. In parallel to glycolysis, G6P can also enter the pentose phosphate pathway (PPP) in the cytosol, where G6P is converted into ribose for RNA synthesis, NADPH production and reactive oxygen species (ROS) generation. This pathway is also necessary to reduce glutathione (GSH), an antioxidant and ROS Cells 2020, 9, 562; doi:10.3390/cells9030562 www.mdpi.com/journal/cells Cells 2020, 9, 562 2 of 22 Cells 2020, 9, 562 2 of 22 scavenger that is crucial to protect pro-inflammatory immune cells from incurring damage from increasedscavenger ROS that production is crucial to [5 ].protect In the pro oxidative-inflammatory phase, immune G6P is cells converted from incurring to ribulose-5-phosphate damage from by 6-phosphogluconateincreased ROS production dehydrogenase [5]. In the oxidative (PGD) phase, for NADPH G6P is converted production, to ribulose which-5- isphosphate not only by used by NADPH6-phosphogluconate oxidase (NOX) dehydrogenase to generate (PGD) ROS for [6], NADPH but is alsoproduction, utilized which for fatty is not acid only biosynthesis used by in NADPH oxidase (NOX) to generate ROS [6], but is also utilized for fatty acid biosynthesis in the the prostaglandin production, plasma membrane synthesis, and phagocytic function in phagocytic prostaglandin production, plasma membrane synthesis, and phagocytic function in phagocytic cells cells [7,8]. Furthermore, the generation of ribose-5-phosphate serves as a precursor for nucleotides [7,8]. Furthermore, the generation of ribose-5-phosphate serves as a precursor for nucleotides and and amino acids, which have roles in many other biosynthetic functions that will be described below. amino acids, which have roles in many other biosynthetic functions that will be described below. PyruvatePyruvate can entercan enter the mitochondria the mitochondria and be and catabolized be catabolized by pyruvate by pyruvate dehydrogenase dehydrogenase into acetyl-CoA. into Acetyl-CoAacetyl-CoA. shuttles Acetyl into-CoA the shuttles tricarboxylic into the acid tricarboxylic (TCA) cycle acid as (TCA) fuel for cycle the productionas fuel for the of production citrate, isocitrate, of alpha-ketoglutaratecitrate, isocitrate, (αalpha-KG),-ketoglutarate succinyl-CoA, (α- succinate,KG), succinyl fumarate,-CoA, succinate, malate, and fumarate, oxaloacetate malate, (Figure and 1). Whileoxaloacetate successful (Figure completion 1). While ofthe successful TCA cycle completion and electron of the transportTCA cycle chainand electron results transport in a net gainchain of 36 moleculesresults ofin ATP,a net these gain TCAof 36 cyclemolecules intermediates of ATP, these are also TCA known cycle tointermediates participate inare metabolic also known processes to outsideparticipate of ATP in production. metabolic processes Prominent outside examples of ATP of production. this are citrate Prominent and succinate examples metabolism.of this are citrate Citrate, producedand succinate from oxaloacetate metabolism. and Citrate, acetyl-CoA, produced can from escape oxaloacetate the mitochondria and acetyl through-CoA, can the mitochondrialescape the citratemitochondria carrier (SLC25A1). through the Once mitochondrial in the cytosol, citrate citrate carrier can (SLC25A1). be used in Once the production in the cytosol, of nitric citrate oxide can be (NO), ROS,used prostaglandin in the production E2 (PGE2), of nitric and oxide cytosol (NO), acetyl-CoA ROS, prostaglandin which are E2 crucial (PGE2), for and modulating cytosol acetyl inflammatory-CoA which are crucial for modulating inflammatory responses [9,10]. Similarly, succinate entering the responses [9,10]. Similarly, succinate entering the cytosol can be used as a cue to inhibit the activity of cytosol can be used as a cue to inhibit the activity of HIF-1α prolyl hydroxylase (PHD) and aid HIF-1α prolyl hydroxylase (PHD) and aid HIF-1α-stabilization. This in turn, increases expression of HIF-1α-stabilization. This in turn, increases expression of glycolytic machinery during inflammation glycolytic[11,12]. machinery Thus, TCA duringcycle is inflammationone point of disparity [11,12]. amongst Thus, TCA pro- cycleinflammation is one point and an ofti disparity-inflammation amongst pro-inflammationin immune cells and which anti-inflammation will be discussed inin immunedetail below. cells which will be discussed in detail below. FigureFigure 1. Overview 1. Overview of majorof major carbohydrate carbohydrate metabolicmetabolic pathways. Carbohydrates Carbohydrates are are highlighted highlighted in in red withred with the majorthe major contributions contributions of of the the respective respective pathwayspathways described described in in the the brackets. brackets. ETC, ETC, electron electron transporttransport chain; chain; F-1-P, F- fructose-1-phosphate;1-P, fructose-1-phosphate; F-1,6-BP, F-1,6- fructoseBP, fructose 1,6-bisphosphate; 1,6-bisphosphate; FAD, FAD, flavin flavin adenine dinucleotide;adenine dinucleotide; FAS, fatty acidFAS,synthase; fatty acid s FAO,ynthase fatty; FAO, acid fatty oxidation; acid oxidation; GLS, glutaminase; GLS, glutaminase GLUT1,; GLUT1, glucose transporterglucose 1;transporter NAD, nicotinamide 1; NAD, adenine nicotinamide dinucleotide; adenine OXPHOS, dinucleotide; oxidative OXPHOS, phosphorylation; oxidative PPP, pentosephosphorylation; phosphate pathway; PPP, pentose SGLT1, phosphate sodium /glucosepathway; con-transporter SGLT1, sodium/glucose 1; SLC1A5, con neutral-transporter amino 1; acid SLC1A5, neutral amino acid transporter family 1 member 5; SLC2A5, neutral amino acid transporter transporter family 1 member 5; SLC2A5, neutral amino acid transporter family 2 member 5; TCA, tricarboxylic acid cycle or Krebs cycle; UDPG, uridine diphosphate-glucose. Cells 2020, 9, 562 3 of 22 TCA cycle generates the reducing equivalents NADH and FADH2 which are essential to support the activity of mitochondrial respiratory chain, also known as the electron transport chain (ETC). The ETC is composed of four large multiprotein complexes (complex I to IV), and two diffusible electron carriers (cytochrome C and ubiquinone) in the inner membrane of mitochondrion. It is known that Toll-like receptor (TLR) activation via tumor necrosis factor receptor-associated factor 6 (TRAF6) translocation to the mitochondria interacts with evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT) to promote mitochondrial ROS (mtROS) production and the recruitment of the mitochondria to phagosomes [13]. The complexes of the ETC except for complex II (or Succinate dehydrogenase (SDH)) are able to form supercomplexes in the mitochondrial inner membrane which limit excessive mtROS formation from the respiratory chain [14]. The oxidation of succinate
Load more

Recommended publications
  • PYGL Rabbit Polyclonal Antibody
    PYGL Rabbit Polyclonal Antibody CAB6710 Product Information Protein Background Size: This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1, 4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from 20uL, 50uL, 100uL, 200uL inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal Observed MW: controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that 110kDa are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just Calculated MW: those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in 93kDa/97kDa moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms. Applications: WB IF IP Immunogen information Reactivity: Gene ID: 5836 Human, Mouse, Rat Uniprot P06737 Antibody Information Recommended dilutions: Synonyms: WB 1:500 - 1:2000 IF 1:50 - PYGL; GSD6 1:200 IP 1:50 - 1:200 Source: Rabbit Immunogen: Recombinant fusion protein containing a sequence corresponding Isotype: to amino acids 1-280 of human PYGL (NP_002854.3). IgG Storage: Store at -20℃. Avoid freeze / thaw cycles. Buffer: PBS with 0.02% sodium azide, 50% glycerol, pH7.3. Purification: Affinity purification Copyright © 2021 Assay Genie [email protected] www.assaygenie.com Product Images Western blot analysis of extracts of various cell lines, using PYGL antibody (CAB6710) at 1:1000 dilution.
    [Show full text]
  • Molecular Diagnosis of Glycogen Storage Disease and Disorders with Overlapping Clinical Symptoms by Massive Parallel Sequencing
    © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing Ana I Vega, PhD1,2,3, Celia Medrano, BSc1,2,3, Rosa Navarrete, BSc1,2,3, Lourdes R Desviat, PhD1,2,3, Begoña Merinero, PhD1,2,3, Pilar Rodríguez-Pombo, PhD1,2,3, Isidro Vitoria, MD, PhD4, Magdalena Ugarte, PhD1,2,3, Celia Pérez-Cerdá, PhD1,2,3 and Belen Pérez, PhD1,2,3 Purpose: Glycogen storage disease (GSD) is an umbrella term for a Results: Pathogenic mutations were detected in 23 patients. group of genetic disorders that involve the abnormal metabolism of ­Twenty-two mutations were recognized (mostly loss-of-function glycogen; to date, 23 types of GSD have been identified. The nonspe- mutations), including 11 that were novel in GSD-associated genes. In cific clinical presentation of GSD and the lack of specific biomarkers addition, CES detected five patients with mutations in ALDOB, LIPA, mean that Sanger sequencing is now widely relied on for making a NKX2-5, CPT2, or ANO5. Although these genes are not involved in diagnosis. However, this gene-by-gene sequencing technique is both GSD, they are associated with overlapping phenotypic characteristics laborious and costly, which is a consequence of the number of genes such as hepatic, muscular, and cardiac dysfunction. to be sequenced and the large size of some genes. Conclusions: These results show that next-generation sequenc- ing, in combination with the detection of biochemical and clinical Methods: This work reports the use of massive parallel sequencing hallmarks, provides an accurate, high-throughput means of making to diagnose patients at our laboratory in Spain using either a cus- genetic diagnoses of GSD and related diseases.
    [Show full text]
  • Six Glycolysis-Related Genes As Prognostic Risk Markers Can Predict the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma
    Hindawi BioMed Research International Volume 2021, Article ID 8824195, 13 pages https://doi.org/10.1155/2021/8824195 Research Article Six Glycolysis-Related Genes as Prognostic Risk Markers Can Predict the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma LangXiong Chen ,1,2 XiaoSong He,1,2 ShiJiang Yi,1,2 GuanCheng Liu,1,2 Yi Liu,1,2 and YueFu Ling 1,2 1Otolaryngology & Head and Neck Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China 2The Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China Correspondence should be addressed to YueFu Ling; [email protected] Received 19 September 2020; Revised 10 January 2021; Accepted 15 January 2021; Published 10 February 2021 Academic Editor: R. K. Tripathy Copyright © 2021 LangXiong Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Head and neck squamous cell carcinoma (HNSCC) is one of the worst-prognosis malignant tumors. This study used bioinformatic analysis of the transcriptome sequencing data of HNSCC and the patients’ survival and clinical data to construct a prediction signature of glycolysis-related genes as the prognostic risk markers. Methods. Gene expression profile data about HNSCC tissues (n = 498) and normal tissues in the head and neck (n =44) were got from The Cancer Genome Atlas (TCGA), as well as patients’ survival and clinical data. Then, we obtained core genes; their expression in head and neck squamous cell carcinoma tissues is significantly different from that in normal head and neck tissues.
    [Show full text]
  • Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease
    cells Review Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease Marta Migocka-Patrzałek * and Magdalena Elias Department of Animal Developmental Biology, Faculty of Biological Sciences, University of Wroclaw, 50-335 Wroclaw, Poland; [email protected] * Correspondence: [email protected] Abstract: Glycogen phosphorylase (PG) is a key enzyme taking part in the first step of glycogenolysis. Muscle glycogen phosphorylase (PYGM) differs from other PG isoforms in expression pattern and biochemical properties. The main role of PYGM is providing sufficient energy for muscle contraction. However, it is expressed in tissues other than muscle, such as the brain, lymphoid tissues, and blood. PYGM is important not only in glycogen metabolism, but also in such diverse processes as the insulin and glucagon signaling pathway, insulin resistance, necroptosis, immune response, and phototransduction. PYGM is implicated in several pathological states, such as muscle glycogen phosphorylase deficiency (McArdle disease), schizophrenia, and cancer. Here we attempt to analyze the available data regarding the protein partners of PYGM to shed light on its possible interactions and functions. We also underline the potential for zebrafish to become a convenient and applicable model to study PYGM functions, especially because of its unique features that can complement data obtained from other approaches. Keywords: PYGM; muscle glycogen phosphorylase; functional protein partners; glycogenolysis; McArdle disease; cancer; schizophrenia Citation: Migocka-Patrzałek, M.; Elias, M. Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease. Cells 1. Introduction 2021, 10, 883. https://doi.org/ The main energy substrate in animal tissues is glucose, which is stored in the liver and 10.3390/cells10040883 muscles in the form of glycogen, a polymer consisting of glucose molecules.
    [Show full text]
  • Linking Glycogen and Senescence in Cancer Cells
    Cell Metabolism Previews Linking Glycogen and Senescence in Cancer Cells Susana Ros1 and Almut Schulze1,* 1Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2012.11.010 Glycogen metabolism operates as an alternative energy source, enabling cell growth under conditions of metabolic stress. Favaro et al. (2012) now demonstrate that in hypoxic cancer cells, depletion of liver glycogen phosphorylase causes glycogen accumulation, leading to oxidative stress, induction of senes- cence, and impaired tumor growth in vivo. Among the various metabolic adaptations (PYGL) was previously found among the the survival of cancer cells (Figure 1). employed by cancer cells to adjust to the 99 genes included in a hypoxia ‘‘meta- Based on this model, PYGL silencing conditions imposed by the tumor micro- gene’’ signature, which predicts poor impairs glycogen breakdown, results in environment, changes in glycogen meta- survival in head and neck squamous cell decreased flux through the PPP, and bolism are emerging as an essential carcinomas and breast cancer (Winter diminishes NADPH levels, which not only response (Brahimi-Horn et al., 2011). et al., 2007). Therefore, the role of provide the reductive power for the Understanding the role of glycogen glycogen degradation in response to synthesis of macromolecules for cell metabolism in neoplastic transformation hypoxia and in cancer cell survival re- growth and proliferation, but also main- requires a better knowledge of how this mained unclear. tain cellular redox balance. The increase metabolic pathway is regulated in cancer.
    [Show full text]
  • Extracellular Vesicles Released By
    Published OnlineFirst October 25, 2017; DOI: 10.1158/1078-0432.CCR-17-2046 Cancer Therapy: Preclinical Clinical Cancer Research Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury Chontida Yarana1,2, Dustin Carroll1, Jing Chen3, Luksana Chaiswing1, Yanming Zhao1, Teresa Noel1, Michael Alstott4, Younsoo Bae5, Emily V. Dressler6, Jeffrey A. Moscow7, D. Allan Butterfield4,8, Haining Zhu1,3,4, and Daret K. St. Clair1 Abstract Purpose: Cardiac injury is a major cause of death in cancer tinctive presence of brain/heart, muscle, and liver isoforms of survivors, and biomarkers for it are detectable only after tissue glycogen phosphorylase (GP), and their origins were verified to injury has occurred. Extracellular vesicles (EV) remove toxic be heart, skeletal muscle, and liver, respectively. The presence of biomolecules from tissues and can be detected in the blood. brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of Here, we evaluate the potential of using circulating EVs as early PYGB in heart, but not brain tissues. Manganese superoxide dis- diagnostic markers for long-term cardiac injury. mutase (MnSOD) overexpression, as well as pretreatment with Experimental Design: Using a mouse model of doxorubicin cardioprotective agents and MnSOD mimetics, resulted in a reduc- (DOX)-induced cardiac injury, we quantified serum EVs, analyzed tion of EV-associated PYGB in mice treated with DOX. Kinetic proteomes, measured oxidized protein levels in serum EVs released studies indicated that EVs containing PYGB were released prior to after DOX treatment, and investigated the alteration of EV content. the rise of cardiac troponin in the blood after DOX treatment, Results: Treatment with DOX caused a significant increase in suggesting that PYGB is an early indicator of cardiac injury.
    [Show full text]
  • Targeting Glycogen Metabolism: a Novel Strategy to Inhibit Cancer Cell Growth?
    www.impactjournals.com/oncotarget/ Oncotarget, January, Vol.4, No 1 Targeting glycogen metabolism: a novel strategy to inhibit cancer cell growth? Elena Favaro and Adrian L. Harris Metabolic reprogramming in cancer cells provides is that glycogen performs important signaling roles energy and important metabolites required to sustain within cells. For example, AMP-activated protein kinase tumor proliferation [1]. In our recent paper in Cell (AMPK), which is an important regulator of cellular Metabolism, we demonstrate that glycogen mobilization energy homeostasis, is directly inhibited by highly is a common feature of cancer cell metabolism, and may branched glycogen granules [6]. therefore represent a novel anticancer therapeutic target Of clinical significance, our findings implicate [2]. Glycogen primarily acts as an intracellular storage glycogen metabolizing enzymes, and PYGL in particular, of glucose and fulfills important roles (in both non- as promising possible targets for cancer treatment. Indeed, malignant and cancer cells) under conditions of oxygen some of these treatments may already exist, as PYGL and nutrient deprivation. Glycogen phosphorylase is the inhibitors are already in development for the treatment of main enzyme that catalyzes the release of glucose from type 2 diabetes. Although there are no data available in glycogen. Interestingly, we demonstrated that the liver humans, these agents are unlikely to be toxic to most cells isoform of glycogen phosphorylase, PYGL, is upregulated because patients affected by Hers’ disease (an inherited in hypoxia, and is required for glycogen breakdown in glycogen storage disorder caused by deficiency of PYGL) both tumor xenografts and in cancer cell lines. PYGL are largely asymptomatic. Furthermore, based on our depletion leads to glycogen accumulation, impaired redox observations, a number of combination therapies could balance, and a reduction in proliferation due to p53- also be considered.
    [Show full text]
  • Supplementary Table 2: Energy Metabolism Related Genes
    Supplementary table 2: Energy metabolism related genes Gene Gene title Fold change Regulation in Corr. Probe Set ID Symbol GLT1+ vs. Thy1+ GLT1+ cells P-value Aco1 Aconitase 1 2.4 up 0.0051 1423644_at Aco2 Aconitase 2, mitochondrial 2.0 up 0.0119 1451002_at Aldoa Aldolase 1, a isoform 1.5 up 0.0428 1434799_x_at Aldoc Aldolase 3, c isoform 118.7 up 0.0001 1424714_at Bpgm 2,3-bisphosphoglycerate mutase 2.3 up 0.2119 1415864_at Cs Citrate synthase 2.2 up 0.0091 1422578_at Dlst Dihydrolipoamide s-succinyltransferase 1.0 up 0.9344 1423710_at Eno1 Enolase 1, alpha non-neuron 50.2 up 0.0107 1419022_a_at Eno2 Enolase 2, gamma neuronal 2.2 down 0.0113 1418829_a_at Fh1 Fumarate hydratase 1 2.5 up 0.0062 1424828_a_at G6pdx Glucose-6-phosphate dehydrogenase x-linked 1.7 up 0.1096 1448354_at Gad1 Glutamic acid decarboxylase 1 17.2 down 0.0016 1416561_at Gls Glutaminase 1.7 down 0.0062 1434657_at Glud1 Glutamate dehydrogenase 1 4.3 up 0.0023 1448253_at Glul Glutamate-ammonia ligase (glutamine synthetase) 3.3 up 0.0023 1426235_a_at Got1 Glutamate oxaloacetate transaminase 1, soluble 3.2 up 0.0171 1450970_at Got2 Glutamate oxaloacetate transaminase 2, 1.5 down 0.2135 1430397_at mitochondrial Gpd1 Glycerol-3-phosphate dehydrogenase 1 (soluble) 1.7 down 0.0607 1416204_at Gpd1l Glycerol-3-phosphate dehydrogenase 1-like 1.7 up 0.0879 1438195_at Gpd2 Glycerol phosphate dehydrogenase 2, mitochondrial 1.9 up 0.0231 1452741_s_at Gpi1 Glucose phosphate isomerase 1 2.3 up 0.0128 1434814_x_at Gys1 Glycogen synthase 1, muscle 4.4 up 0.0187 1450196_s_at Hk1 Hexokinase
    [Show full text]
  • Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth
    Published OnlineFirst October 4, 2019; DOI: 10.1158/0008-5472.CAN-18-2994 Cancer Translational Science Research Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth Marco Maruggi1, Fabiana Izidro Layng1, Robert Lemos Jr1, Guillermina Garcia1, Brian P. James1, Monica Sevilla1, Ferran Soldevilla2, Bas J. Baaten2, Petrus R. de Jong1, Mei Yee Koh3, and Garth Powis1 Abstract Cancer cells respond to hypoxia by upregulating the tumors identified hypoxic cancer cells with inhibited gly- hypoxia-inducible factor 1a (HIF1A) transcription factor, cogen breakdown, which promoted glycogen accumulation which drives survival mechanisms that include metabolic and the secretion of inflammatory cytokines, including adaptation and induction of angiogenesis by VEGF. Pan- interleukins 1b (IL1B) and 8 (IL8). scRNA-seq of the mouse creatic tumors are poorly vascularized and severely hypoxic. tumor stroma showed enrichment of two subsets of myeloid To study the angiogenic role of HIF1A, and specifically dendritic cells (cDC), cDC1 and cDC2, that secreted proan- probe whether tumors are able to use alternative pathways giogenic cytokines. These results suggest that glycogen in its absence, we created a xenograft mouse tumor model of accumulation associated with a clear-cell phenotype in pancreatic cancer lacking HIF1A. After an initial delay of hypoxic cancer cells lacking HIF1A can initiate an alternate about 30 days, the HIF1A-deficient tumors grew as rapidly pathway of cytokine and DC-driven angiogenesis. Inhibiting as the wild-type tumors and had similar vascularization. glycogen accumulation may provide a treatment for cancers These changes were maintained in subsequent passages of with the clear-cell phenotype.
    [Show full text]
  • PYGL (C3): Sc-517597
    SANTA CRUZ BIOTECHNOLOGY, INC. PYGL (C3): sc-517597 BACKGROUND PRODUCT Glycolysis is an evolutionarily conserved series of ten chemical reactions that Each vial contains 100 µg IgG2a kappa light chain in 1.0 ml of PBS with utilizes eleven enzymes to concomitantly generate pyruvate and ATP from < 0.1% sodium azide, 0.1% gelatin and 5% glycerol. glucose. Phospho-fructose kinase-2/fructose 2,6-bisphosphatase (PFK-2) stim- ulates the synthesis and degradation of fructose 2,6-bisphosphate. Glycogen APPLICATIONS phosphorylase (also known as GP) is an allosteric enzyme important in carbo- PYGL (C3) is recommended for detection of PYGL of mouse and rat origin hydrate metabolism. Its activity is regulated through either noncovalent bind- by Western Blotting (starting dilution 1:200, dilution range 1:100-1:1000). ing of metabolites or by covalent modification. Glycogen phosphorylase cat- alyzes the phosphorylation of glycogen to Glc-1-P. There are three genes which Suitable for use as control antibody for PYGL siRNA (m): sc-45922, PYGL encode the brain, liver and muscle forms of glycogen phosphorylase, PYGB, shRNA Plasmid (m): sc-45922-SH and PYGL shRNA (m) Lentiviral Particles: PYGL and PYGM. Because of its fundamental role in the metabolism of glyco- sc-45922-V. gen, glycogen phosphorylase has been a target for the design of inhibitory Molecular Weight of PYGL: 97 kDa. compounds, which could be valuable in the therapeutic treatment of type 2 diabetes mellitus. RECOMMENDED SUPPORT REAGENTS To ensure optimal results, the following support reagents are recommended: REFERENCES 1) Western Blotting: use m-IgGκ BP-HRP: sc-516102 or m-IgGκ BP-HRP (Cruz 1.
    [Show full text]
  • The Mcardle Disease Handbook a Guide to the Scientific and Medical Research Into Mcardle Disease Explained in Plain English
    The McArdle Disease Handbook A guide to the scientific and medical research into McArdle disease explained in plain English. Written by Kathryn Elizabeth Wright, Ph.D. Copyright ©Kathryn Wright 2010 Disclaimer Unless otherwise stated, this Handbook represents the views and opinions of the author, Kathryn Wright, and does not represent the views and opinions of AGSD (UK) or Vodafone World of Difference. The purpose of this Handbook is to explain scientific research and knowledge about McArdle disease in layman’s language so that it can be understood by people with McArdle disease or those interested in McArdle disease. It is not intended to replace medical advice from your family doctor or specialist. The information provided in this Handbook is correct to the best of the author’s knowledge. If you have any doubts about the accuracy of the information in this Handbook, it is recommended that you read the original source (full details in the reference list). Where no definitive information is available, the author has sought to suggest scientific rationale behind anecdotal observations reported by people with McArdle’s. It is stated where a theory or opinion of the author is given. Due to the nature of scientific research, current theories and understanding of the science behind McArdle’s may change over time and subsequently be proven or disproven. It is recommended that you check the AGSD (UK) website frequently to ensure you are reading the most up-to-date version of this Handbook. Funding for this project Kathryn Wright submitted a proposal and successfully obtained funding from the Vodafone World of Difference charitable foundation under the “World of Difference UK” scheme.
    [Show full text]
  • Glycogen Shortage During Fasting Triggers Liver–Brain–Adipose Neurocircuitry to Facilitate Fat Utilization
    ARTICLE Received 26 Jan 2013 | Accepted 17 Jul 2013 | Published 13 Aug 2013 | Updated 4 Dec 2013 DOI: 10.1038/ncomms3316 OPEN Glycogen shortage during fasting triggers liver–brain–adipose neurocircuitry to facilitate fat utilization Yoshihiko Izumida1,2,3, Naoya Yahagi1,2,4, Yoshinori Takeuchi1,4, Makiko Nishi1,2,4, Akito Shikama1,4, Ayako Takarada1, Yukari Masuda1,2, Midori Kubota1,2, Takashi Matsuzaka4, Yoshimi Nakagawa4, Yoko Iizuka2, Keiji Itaka5, Kazunori Kataoka5, Seiji Shioda3, Akira Niijima6, Tetsuya Yamada7, Hideki Katagiri7, Ryozo Nagai2, Nobuhiro Yamada4, Takashi Kadowaki2 & Hitoshi Shimano4 During fasting, animals maintain their energy balance by shifting their energy source from carbohydrates to triglycerides. However, the trigger for this switch has not yet been entirely elucidated. Here we show that a selective hepatic vagotomy slows the speed of fat consumption by attenuating sympathetic nerve-mediated lipolysis in adipose tissue. Hepatic glycogen pre-loading by the adenoviral overexpression of glycogen synthase or the transcription factor TFE3 abolished this liver–brain–adipose axis activation. Moreover, the blockade of glycogenolysis through the knockdown of the glycogen phosphorylase gene and the resulting elevation in the glycogen content abolished the lipolytic signal from the liver, indicating that glycogen is the key to triggering this neurocircuitry. These results demonstrate that liver glycogen shortage activates a liver–brain–adipose neural axis that has an important role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions. 1 Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan. 2 Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
    [Show full text]