DOCSLIB.ORG

Comparative Analysis of Cerebrospinal Fluid Metabolites in Alzheimer's

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Comparative Analysis of Cerebrospinal Fluid Metabolites in Alzheimer's Nagata et al. Biomarker Research (2018) 6:5 DOI 10.1186/s40364-018-0119-x RESEARCH Open Access Comparative analysis of cerebrospinal fluid metabolites in Alzheimer’s disease and idiopathic normal pressure hydrocephalus in a Japanese cohort Yuki Nagata1* , Akiyoshi Hirayama2, Satsuki Ikeda2, Aoi Shirahata2, Futaba Shoji2, Midori Maruyama2, Mitsunori Kayano3, Masahiko Bundo4, Kotaro Hattori5, Sumiko Yoshida5, Yu-ichi Goto5, Katsuya Urakami6, Tomoyoshi Soga2, Kouichi Ozaki1 and Shumpei Niida1 Abstract Background: Alzheimer’s disease (AD) is a most common dementia in elderly people. Since AD symptoms resemble those of other neurodegenerative diseases, including idiopathic normal pressure hydrocephalus (iNPH), it is difficult to distinguish AD from iNPH for a precise and early diagnosis. iNPH is caused by the accumulation of cerebrospinal fluid (CSF) and involves gait disturbance, urinary incontinence, and dementia. iNPH is treatable with shunt operation which removes accumulated CSF from the brain ventricles. Methods: We performed metabolomic analysis in the CSF of patients with AD and iNPH with capillary electrophoresis-mass spectrometry. We assessed metabolites to discriminate between AD and iNPH with Welch’s t-test, receiver operating characteristic (ROC) curve analysis, and multiple logistic regression analysis. Results: We found significant increased levels of glycerate and N-acetylneuraminate and significant decreased levels of serine and 2-hydroxybutyrate in the CSF of patients with AD compared to the CSF of patients with iNPH. The ROC curve analysis with these four metabolites showed that the area under the ROC curve was 0.90, indicating good discrimination between AD and iNPH. Conclusions: This study identified four metabolites that could possibly discriminate between AD and iNPH, whichpreviousresearchhasshownarecloselyrelatedto the risk factors, pathogenesis, and symptoms of AD. Analyzing pathway-specific metabolites in the CSF of patients with AD may further elucidate the mechanism and pathogenesis of AD. Keywords: Alzheimer’s disease, Idiopathic normal pressure hydrocephalus, Diagnostic marker, Cerebrospinal fluid, Serine, Glycerate, N-acetylneuraminate, 2-hydroxybutyrate Background according to the National Institute of Neurological Alzheimer’s disease (AD) is the most common type of de- and Communicative Disorders and Stroke and the mentia in the world, which concerns approximately 60–70% Alzheimer’s Disease and Related Disorders Association cases of dementia, and it is becoming a significant social criteria [1]. Currently, there is no curative or radical issue because of the growing aging population. treatment for AD, although some medicines have In general, AD is diagnosed based on the presence of been developed to reduce the symptoms [2]. However, cognitive impairment and by neuropsychological testing some symptoms of AD are similar to those of other neurodegenerative diseases, such as idiopathic normal * Correspondence: [email protected] pressure hydrocephalus (iNPH). iNPH is caused by the accu- 1Medical Genome Center, National Center for Geriatrics and Gerontology, mulation of cerebrospinal fluid (CSF) in the brain and causes 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan Full list of author information is available at the end of the article gait disturbance, urinary incontinence, and dementia. In © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nagata et al. Biomarker Research (2018) 6:5 Page 2 of 11 contrast to other dementias, iNPH is treatable by shunt op- at different AD stages and found that choline, dimethylar- eration that removes the accumulated CSF [3]. Therefore, a ginine, arginine, valine, proline, serine, histidine, creatine, precise diagnosis that discriminates patients with AD from carnitine, and suberylglycine could be possible disease patients with iNPH is essential for proper treatment at the progression markers [16]. Furthermore, they conducted early stages of these diseases. Presently, increased phosphate ultra-high-performance liquid chromatography-time-of- tau (p-tau) and decreased amyloid-beta 1-42 (Aβ42) in the flight mass spectrometry (TOFMS) and found uracil and CSF are used as established AD diagnostic markers [4]. uridine were good candidate biomarkers for AD, as has However, p-tau accumulates after synaptic degeneration and been previously described [15, 17]. Aβ42 is difficult to accurately quantify. Therefore, we tried to However, different metabolomic platforms and methods find additional biomarkers, capable of precisely detecting AD detect different metabolites, thus utilizing multiple types before neurodegeneration progresses. of metabolomic platforms would provide a wider perspec- Recently, accumulated evidence has indicated that tive of metabolomics information under study. In addition, AD is a type of metabolic disease in the brain [5, 6]. differences in ethnicity, culture, and education may influ- The brain is the most energy-consuming organ and ence decision making regarding the diagnosis, symptoms, glucose is an essential and dominant energy source and severity of AD [18]. Accordingly, accumulating infor- for the brain [7]. Progressive regional cerebral glu- mation related to AD pathology from differential ethnora- cose metabolism reduction, correlated with the cial cohorts and with differential methods is essential. symptom severity, has been found in the brain of pa- From these points of view, we performed metabolo- tients with AD [8, 9]. Mills et al. (2013) performed micanalysisoftheCSFofpatientswithADoriNPH RNA-Seq analysis in the parietal cortex of patients in Japanese cohorts with capillary electrophoresis- with AD and reported that two enzymes, ACOT1 TOFMS (CE-TOFMS). Our present findings would and ACOT2, which are involved in lipid metabolism, support the utility of metabolomics analysis for dis- were upregulated. They also found a downregulation criminate between AD and iNPH. of TERC, which is involved in the synthesis of very long chain fatty acids [10]. In addition, impairment Methods of the insulin response, as is seen in diabetes melli- Subjects tus and metabolic syndrome, was revealed as a risk The characteristics of the study patients with AD and factor for AD [11–13]. These reports suggested that iNPH are summarized in Table 1. AD and iNPH were the pathomechanism of AD is strongly related to a diagnosed according to previously published criteria [1, disturbance in brain energy metabolism and homeo- 19]. Bioresources were largely obtained from the biobank stasis. The disturbance could induce metabolite al- of the National Center for Geriatrics and Gerontology terations in the body fluids of patients with AD, (NCGG, Aichi, Japan) and partly donated by the such as in the plasma, serum, and CSF. Therefore, National Center of Neurology and Psychiatry (NCNP, metabolome analysis of body fluids in AD has been Tokyo, Japan) and the Department of Biological Regulation, actively performed to identify new diagnostic School of Medicine, Tottori University (Tottori, Japan). All markers. Especially, the CSF is thought to be a su- samples were obtained with the written informed consent of perior analyte than other body fluids because it is in the patients before sampling between 2011 and 2015. This direct contact with the extracellular space of the study was reviewed and approved by the ethics committees brain and thus directly reflects the biological of all participating institutes and biobanks. changes in the pathological brain processes in AD. So far, several pertinent reports have been pub- Table 1 Subject characteristics. lished and several diagnostic markers for AD have Metabolomics Validation been suggested. For example, D’ Aniello et al. (2005) AD iNPH AD iNPH conducted high performance liquid chromatography Subject No. 39 19 42 38 (HPLC) analysis and found L-glutamine was in- Mean age (SD) 73.5 (9.8) 77.8 (4.5) 74.1 (9.6) 77.9 (5.6) creased and L-asparate was decreased in the CSF of Age range 47-86 70-86 47-86 57-87 patients with AD than in the CSF of controls [14]. Czech et al. (2012) reported that increased cysteine P-value 0.03 0.03 with decreased uridine was the optimal combination Male/female 14/25 9/10 15/27 22/16 to identify mild AD, and increased cortisol levels P-value 0.24 0.09 were associated with the progression of AD in a Mean MMSE (SD) 21.4 (5.1) 23.5 (2.9) 21.2 (5.0) 22.1 (3.1) European cohort [15]. Ibanez et al. (2012) performed P-value 0.08 0.46 capillary electrophoresis-mass spectrometry (CE-MS) Missing values 6 0 6 0 to investigate metabolome changes in the CSF of patients Nagata et al. Biomarker Research (2018) 6:5 Page 3 of 11 Collection of CSF delivered as sheath liquid at 10 L/min. ESI-TOFMS was op- CSF was collected by lumbar puncture and centrifuged erated in the positive ion mode, and the capillary voltage to remove debris. The supernatant was aliquoted into was set at 4 kV. The flow rate of heated nitrogen gas low protein-binding tubes and immediately frozen in li- (heater temperature, 300 °C) was maintained at 10 psig. In quid nitrogen and stored at −80 °C until use. TOFMS, the fragmentor, skimmer, and Oct RF voltages were set at 75, 50, and 125 V, respectively. Automatic recal- Measurement of p-tau and Aβ42 ibration of each acquired spectrum was performed using To detect the concentration of p-tau and Aβ42 in the the masses of reference standards ([13C isotopic ion of pro- + CSF, the enzyme-linked immunosorbent assay systems of tonated methanol dimer (2CH3OH + H)] , m/z 66.06306) + INNOTEST β-AMYLOID(1-42) and INNOTEST PHOSPHO- and ([hexakis(2,2-difluoroethoxy)phosphazene + H] , m/z TAU(181P) were used according to the manufacturer’sinstruc- 622.02896).
Load more

Recommended publications
  • Inflammatory Stimuli Induce Acyl-Coa Thioesterase 7 and Remodeling of Phospholipids Containing Unsaturated Long (C20)-Acyl Chains in Macrophages
    Supplemental Material can be found at: http://www.jlr.org/content/suppl/2017/04/17/jlr.M076489.DC1 .html Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (C20)-acyl chains in macrophages Valerie Z. Wall,*,† Shelley Barnhart,* Farah Kramer,* Jenny E. Kanter,* Anuradha Vivekanandan-Giri,§ Subramaniam Pennathur,§ Chiara Bolego,** Jessica M. Ellis,§§,*** Miguel A. Gijón,††† Michael J. Wolfgang,*** and Karin E. Bornfeldt1,*,† Department of Medicine,* Division of Metabolism, Endocrinology and Nutrition, and Department of Pathology,† UW Medicine Diabetes Institute, University of Washington, Seattle, WA; Department of Internal Medicine,§ University of Michigan, Ann Arbor, MI; Department of Pharmaceutical and Pharmacological Sciences,** University of Padova, Padova, Italy; Department of Nutrition Science,§§ Purdue University, West Lafayette, IN; Department of Biological Chemistry,*** Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Pharmacology,††† University of Downloaded from Colorado Denver, Aurora, CO Abstract Acyl-CoA thioesterase 7 (ACOT7) is an intracel- containing unsaturated long (C20)-acyl chains in macro- lular enzyme that converts acyl-CoAs to FFAs. ACOT7 is in- phages, and, although ACOT7 has preferential thioesterase duced by lipopolysaccharide (LPS); thus, we investigated activity toward these lipid species, loss of ACOT7 has no ma- www.jlr.org downstream effects of LPS-induced induction of ACOT7 jor detrimental effect on macrophage inflammatory pheno- and its role in inflammatory settings in myeloid cells. Enzy- types.—Wall, V. Z., S. Barnhart, F. Kramer, J. E. Kanter, matic thioesterase activity assays in WT and ACOT7-deficient A. Vivekanandan-Giri, S. Pennathur, C. Bolego, J. M. Ellis, macrophage lysates indicated that endogenous ACOT7 con- M.
    [Show full text]
  • The Metabolic Serine Hydrolases and Their Functions in Mammalian Physiology and Disease Jonathan Z
    REVIEW pubs.acs.org/CR The Metabolic Serine Hydrolases and Their Functions in Mammalian Physiology and Disease Jonathan Z. Long* and Benjamin F. Cravatt* The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States CONTENTS 2.4. Other Phospholipases 6034 1. Introduction 6023 2.4.1. LIPG (Endothelial Lipase) 6034 2. Small-Molecule Hydrolases 6023 2.4.2. PLA1A (Phosphatidylserine-Specific 2.1. Intracellular Neutral Lipases 6023 PLA1) 6035 2.1.1. LIPE (Hormone-Sensitive Lipase) 6024 2.4.3. LIPH and LIPI (Phosphatidic Acid-Specific 2.1.2. PNPLA2 (Adipose Triglyceride Lipase) 6024 PLA1R and β) 6035 2.1.3. MGLL (Monoacylglycerol Lipase) 6025 2.4.4. PLB1 (Phospholipase B) 6035 2.1.4. DAGLA and DAGLB (Diacylglycerol Lipase 2.4.5. DDHD1 and DDHD2 (DDHD Domain R and β) 6026 Containing 1 and 2) 6035 2.1.5. CES3 (Carboxylesterase 3) 6026 2.4.6. ABHD4 (Alpha/Beta Hydrolase Domain 2.1.6. AADACL1 (Arylacetamide Deacetylase-like 1) 6026 Containing 4) 6036 2.1.7. ABHD6 (Alpha/Beta Hydrolase Domain 2.5. Small-Molecule Amidases 6036 Containing 6) 6027 2.5.1. FAAH and FAAH2 (Fatty Acid Amide 2.1.8. ABHD12 (Alpha/Beta Hydrolase Domain Hydrolase and FAAH2) 6036 Containing 12) 6027 2.5.2. AFMID (Arylformamidase) 6037 2.2. Extracellular Neutral Lipases 6027 2.6. Acyl-CoA Hydrolases 6037 2.2.1. PNLIP (Pancreatic Lipase) 6028 2.6.1. FASN (Fatty Acid Synthase) 6037 2.2.2. PNLIPRP1 and PNLIPR2 (Pancreatic 2.6.2.
    [Show full text]
  • Flawed Phospholipid Formation Or Faulty Fatty Acid Oxidation: Determining the Cause of Mitochondrial Dysfunction in Hearts Lacking Acsl1
    FLAWED PHOSPHOLIPID FORMATION OR FAULTY FATTY ACID OXIDATION: DETERMINING THE CAUSE OF MITOCHONDRIAL DYSFUNCTION IN HEARTS LACKING ACSL1 Trisha J. Grevengoed A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition (Biochemistry) in the School of Public Health. Chapel Hill 2015 Approved by: Rosalind A. Coleman Stephen D. Hursting Liza Makowski Leslie V. Parise Steven H. Zeisel © 2015 Trisha J. Grevengoed ALL RIGHTS RESERVED ii ABSTRACT Trisha J. Grevengoed: Fatty acid activation in cardiac mitochondria: The role of ACSL1 in phospholipid formation and remodeling, substrate switching, and autophagic flux (Under the direction of Rosalind A. Coleman) Cardiovascular disease is the number one cause of death worldwide. In the heart, mitochondria provide up to 95% of energy, with most of this energy coming from metabolism of fatty acids (FA). FA must be converted to acyl-CoAs by acyl-CoA synthetases (ACS) before entry into pathways of β- oxidation or glycerolipid synthesis. ACSL1 contributes more than 90% of total cardiac ACSL activity, and mice with an inducible knockout of ACSL1 (Acsl1T-/-) have impaired cardiac FA oxidation. The effects of loss of ACSL1 on mitochondrial respiratory function, phospholipid formation, or autophagic flux have not yet been studied. Acsl1T-/- hearts contained 3-fold more mitochondria with abnormal structure and displayed lower respiratory function. Because ACSL1 exhibited a strong substrate preference for linoleate (18:2), we investigated the composition of mitochondrial phospholipids. Acsl1T-/- hearts contained 83% less tetralinoleoyl-cardiolipin (CL), the major form present in control hearts.
    [Show full text]
  • The Acyl-Coa Thioesterase I (Acot1)
    Technological University Dublin ARROW@TU Dublin Articles School of Biological Sciences 2007-05-01 The acyl-CoA thioesterase I (Acot1) is regulated by the peroxisome proliferator-activated receptor alpha and hepatocyte nuclear factor 4 alpha via a distal response element in the promotor. Bikesh Dongol Karolinska Institute Yatrik Shah National Institutes of Health Insook Kim National Institutes of Health Follow this and additional works at: https://arrow.tudublin.ie/scschbioart See next page for additional authors Part of the Genetics and Genomics Commons Recommended Citation Dongol,B., Shah, Y., Kim, I., Gonzalez, F., Hunt, M. (2007) The acyl-CoA thioesterase I (Acot1) is regulated by the peroxisome proliferator-activated receptor alpha and hepatocyte nuclear factor 4 alpha via a distal response element in the promotor. Journal of Lipid Research. 2007 48:(8) pp.1781-1791. doi:10.1194/ jlr.M700119-JLR200 This Article is brought to you for free and open access by the School of Biological Sciences at ARROW@TU Dublin. It has been accepted for inclusion in Articles by an authorized administrator of ARROW@TU Dublin. For more information, please contact [email protected], [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License Authors Bikesh Dongol, Yatrik Shah, Insook Kim, Frank J. Gonzalez, and Mary Hunt This article is available at ARROW@TU Dublin: https://arrow.tudublin.ie/scschbioart/5 1 The acyl-CoA thioesterase I (Acot1) is regulated by the peroxisome proliferator-activated receptor alpha and hepatocyte nuclear factor 4 alpha via a distal response element in the promotor.
    [Show full text]
  • A Revised Nomenclature for Mammalian Acyl-Coa Thioesterases/Hydrolases Mary Hunt Dublin Institute of Technology, [email protected]
    Dublin Institute of Technology ARROW@DIT Articles School of Biological Sciences 2005-06-01 A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases Mary Hunt Dublin Institute of Technology, [email protected] Junji Yamada Tokyo University of Pharmacy and Life Science Lois Maltais The Jackson Laboratory Mathew Wright University College London Ernesto Podesta University of Buenos Aires See next page for additional authors Recommended Citation Hunt, M., Maltais, L., Wright, M., Podesta, E., Alexson, S.:A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases. Journal of Lipid Research, Vol. 45:(10), 2004,pp. 1958-1961. doi:10.1194/jlr.E400002-JLR200 This Article is brought to you for free and open access by the School of Biological Sciences at ARROW@DIT. It has been accepted for inclusion in Articles by an authorized administrator of ARROW@DIT. For more information, please contact [email protected], [email protected]. Authors Mary Hunt, Junji Yamada, Lois Maltais, Mathew Wright, Ernesto Podesta, and Stefan Alexson This article is available at ARROW@DIT: http://arrow.dit.ie/scschbioart/6 1 A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases. #Mary C. Hunt, ##Junji Yamada, §Lois J. Maltais, *Matthew Wright, §§ Ernesto J.Podesta, and #Stefan E. H. Alexson, #Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry C1-74, Karolinska University Hospital at Huddinge, SE- 141 86 Stockholm, Sweden, ##Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan, §The Mouse Genomic Nomenclature Committee (MGNC), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, *University College London, London, UK, §§Department of Biochemistry, School of Medicine, University of Buenos Aires, Argentina.
    [Show full text]
  • Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/10/10/jpet.118.252296.DC1 1521-0103/367/3/494–508$35.00 https://doi.org/10.1124/jpet.118.252296 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 367:494–508, December 2018 Copyright ª 2018 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license. Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators s Jason R. Clapper, Cassandra L. Henry, Micah J. Niphakis, Anna M. Knize, Aundrea R. Coppola, Gabriel M. Simon, Nhi Ngo, Rachel A. Herbst, Dylan M. Herbst, Alex W. Reed, Justin S. Cisar, Olivia D. Weber, Andreu Viader, Jessica P. Alexander, Mark L. Cunningham, Todd K. Jones, Iain P. Fraser, Cheryl A. Grice, R. Alan B. Ezekowitz, ’ Gary P. O Neill, and Jacqueline L. Blankman Downloaded from Abide Therapeutics, San Diego, California Received July 26, 2018; accepted October 5, 2018 ABSTRACT Monoacylglycerol lipase (MGLL) is the primary degradative whether selective MGLL inhibition would affect prostanoid pro- jpet.aspetjournals.org enzyme for the endocannabinoid 2-arachidonoylglycerol (2- duction in several human assays known to be sensitive AG). The first MGLL inhibitors have recently entered clinical to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain development for the treatment of neurologic disorders. To 2-AG content and displayed antinociceptive and antipru- support this clinical path, we report the pharmacological ritic activity in a battery of rodent models (ED50 values of characterization of the highly potent and selective MGLL inhibitor 1–2 mg/kg).
    [Show full text]
  • I STRUCTURE and FUNCTION of the PALMITOYLTRANSFERASE
    STRUCTURE AND FUNCTION OF THE PALMITOYLTRANSFERASE DHHC20 AND THE ACYL COA HYDROLASE MBLAC2 A Dissertation Presented to the Faculty of the Graduate School Of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Martin Ian Paguio Malgapo December 2019 i © 2019 Martin Ian Paguio Malgapo ii STRUCTURE AND FUNCTION OF THE PALMITOYLTRANSFERASE DHHC20 AND THE ACYL COA HYDROLASE MBLAC2 Martin Ian Paguio Malgapo, Ph.D. Cornell University 2019 My graduate research has focused on the enzymology of protein S-palmitoylation, a reversible posttranslational modification catalyzed by DHHC palmitoyltransferases. When I started my thesis work, the structure of DHHC proteins was not known. I sought to purify and crystallize a DHHC protein, identifying DHHC20 as the best target. While working on this project, I came across a protein of unknown function called metallo-β-lactamase domain-containing protein 2 (MBLAC2). A proteomic screen utilizing affinity capture mass spectrometry suggested an interaction between MBLAC2 (bait) and DHHC20 (hit) in HEK-293 cells. This finding interested me initially from the perspective of finding an interactor that could help stabilize DHHC20 into forming better quality crystals as well as discovering a novel protein substrate for DHHC20. I was intrigued by MBLAC2 upon learning that this protein is predicted to be palmitoylated by multiple proteomic screens. Additionally, sequence analysis predicts MBLAC2 to have thioesterase activity. Taken together, studying a potential new thioesterase that is itself palmitoylated was deemed to be a worthwhile project. When the structure of DHHC20 was published in 2017, I decided to switch my efforts to characterizing MBLAC2.
    [Show full text]
  • Structural Basis for Recruitment of Tandem Hotdog Domains in Acyl-Coa Thioesterase 7 and Its Role in Inflammation
    Structural basis for recruitment of tandem hotdog domains in acyl-CoA thioesterase 7 and its role in inflammation Jade K. Forwood*†‡, Anil S. Thakur*, Gregor Guncar*§¶, Mary Marfori*, Dmitri Mouradov*, Weining Meng*§, Jodie Robinson§ʈ, Thomas Huber*, Stuart Kellie*§ʈ, Jennifer L. Martin*§**, David A. Hume*§ʈ**††, and Bostjan Kobe*‡§** *School of Molecular and Microbial Sciences, §Institute for Molecular Bioscience, ʈCooperative Research Centre for Chronic Inflammatory Diseases, and **Australian Research Council Special Research Centre for Functional and Applied Genomics, University of Queensland, Brisbane, Queensland 4072, Australia Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved May 10, 2007 (received for review February 2, 2007) Acyl-CoA thioesterases (Acots) catalyze the hydrolysis of fatty long-chain acyl-CoA substrates with fatty acid chains of 8–16 acyl-CoA to free fatty acid and CoA and thereby regulate lipid carbon atoms (C8–C16) (7, 13). Acot7 contains a pair of fused metabolism and cellular signaling. We present a comprehensive thioesterase domains that share Ϸ30% sequence identity, with each structural and functional characterization of mouse acyl-CoA thio- thioesterase domain predicted to have the hotdog fold structure esterase 7 (Acot7). Whereas prokaryotic homologues possess a with an ␣-helix sausage wrapped by a ␤-sheet bun (14–16). single thioesterase domain, mammalian Acot7 contains a pair of Here, we present the crystal structures of the N- and C- domains in tandem. We determined the crystal structures of both terminal thioesterase domains (N- and C-domains) of mouse the N- and C-terminal domains of the mouse enzyme, and inferred Acot7, refined at 1.8 and 2.4 Å resolution, respectively.
    [Show full text]
  • The Emerging Role of Acyl-Coa Thioesterases and Acyltransferases in Regulating Peroxisomal Lipid Metabolism☆
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1822 (2012) 1397–1410 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism☆ Mary C. Hunt a,⁎, Marina I. Siponen b,1, Stefan E.H. Alexson c a Dublin Institute of Technology, School of Biological Sciences, College of Sciences & Health, Kevin Street, Dublin 8, Ireland b Department of Medical Biochemistry and Biophysics, Structural Genomics Consortium, Karolinska Institutet, SE-171 77 Stockholm, Sweden c Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden article info abstract Article history: The importance of peroxisomes in lipid metabolism is now well established and peroxisomes contain approx- Received 15 November 2011 imately 60 enzymes involved in these lipid metabolic pathways. Several acyl-CoA thioesterase enzymes Received in revised form 3 March 2012 (ACOTs) have been identified in peroxisomes that catalyze the hydrolysis of acyl-CoAs (short-, medium-, Accepted 16 March 2012 long- and very long-chain), bile acid-CoAs, and methyl branched-CoAs, to the free fatty acid and coenzyme Available online 23 March 2012 A. A number of acyltransferase enzymes, which are structurally and functionally related to ACOTs, have also been identified in peroxisomes, which conjugate (or amidate) bile acid-CoAs and acyl-CoAs to amino acids, Keywords: Acyl-CoA thioesterase resulting in the production of amidated bile acids and fatty acids.
    [Show full text]
  • Supplementary Table S1. Relative Change in Proteins Associated with Heme Biosynthesis and Degradation
    Supplementary Table S1. Relative change in proteins associated with heme biosynthesis and degradation. hPXR mPxr–/– Protein Gene RIF/INH INH RIF RIF/INH p Value 5-aminolevulinate synthase Alas1 1.90 2.61 1.05 1.41 0.28 5-aminolevulinate synthase Alas2 0.86 1.38 0.73 1.18 0.018 Delta-aminolevulinic acid Alad 0.96 1.00 1.02 0.95 0.75 dehydratase Porphobilinogen deaminase Hmbs 1.04 0.99 1.10 1.05 0.67 Uroporphyrinogen-III synthase Uros 1.19 1.09 1.31 1.38 0.012 Uroporphyrinogen decarboxylase Urod 0.92 1.03 0.94 0.92 0.33 Oxygen-dependent Cpox 1.13 1.04 1.18 1.15 0.20 coproporphyrinogen-III oxidase, Protoporphyrinogen oxidase Ppox 0.69 0.81 0.85 0.83 0.013 Ferrochelatase, Fech 0.39 0.50 0.88 0.43 0.000002 Heme oxygenase 1 Hmox1 1.15 0.86 0.91 1.11 0.34 Heme oxygenase 2 Hmox2 0.96 0.98 0.89 0.88 0.22 Biliverdin reductase A Blvra 0.84 0.92 0.82 0.92 0.032 UDP-glucuronosyltransferase 1-6 Ugt1a6 1.22 0.96 1.10 1.13 0.30 NADPH--cytochrome P450 Por 1.28 0.92 1.18 1.12 0.019 reductase INH, isoniazid; RIF, rifampicin; RIF/INH, rifampicin and isoniazid. Supplementary Table S2. Relative change in protein nuclear receptors. hPXR mPxr–/– Protein Gene RIF/INH INH RIF RIF/INH p Value Aryl hydrocarbon receptor Ahr 1.09 0.91 1.00 1.26 0.092 Hepatocyte nuclear factor Hnf1a 0.87 0.97 0.82 0.79 0.027 1-alpha Hepatocyte nuclear factor Hnf4a 0.95 1.05 0.97 1.08 0.20 4-alpha Oxysterols receptor LXR- Nr1h3 0.94 1.16 1.03 1.02 0.42 alpha Bile acid receptor Nr1h4 1.05 1.17 0.98 1.19 0.12 Retinoic acid receptor Rxra 0.88 1.03 0.83 0.95 0.12 RXR-alpha Peroxisome proliferator-
    [Show full text]
  • Differential Regulation of Gene Expression by Cholesterol
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/05/25/jpet.116.233312.DC1 1521-0103/358/2/216–229$25.00 http://dx.doi.org/10.1124/jpet.116.233312 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 358:216–229, August 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes s Elizabeth A. Rondini, Zofia Duniec-Dmuchowski, Daniela Cukovic, Alan A. Dombkowski, and Thomas A. Kocarek Institute of Environmental Health Sciences (E.A.R., Z.D.-D., T.A.K.), and Department of Pediatrics, Division of Clinical Pharmacology and Toxicology (D.C., A.A.D.), Wayne State University, Detroit, Michigan Downloaded from Received March 30, 2016; accepted May 24, 2016 ABSTRACT Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), directly, 162 orthologs were found to be differentially coregu- reduce cholesterol biosynthesis but cause the accumulation of lated between the two treatments. Genes involved in cholesterol jpet.aspetjournals.org isoprenoids derived from farnesyl pyrophosphate (FPP), which and unsaturated fatty acid biosynthesis were up-regulated by can modulate the activity of nuclear receptors, including the both inhibitors, consistent with cholesterol depletion; however, constitutive androstane receptor (CAR), farnesoid X receptor, the extent of induction was greater in rat than in mouse hepa- and peroxisome proliferator-activated receptors (PPARs). In tocytes. SQ1 induced several orthologs associated with micro- comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reduc- somal, peroxisomal, and mitochondrial fatty acid oxidation and tase inhibitors (e.g., pravastatin) inhibit production of both repressed orthologs involved in cell cycle regulation.
    [Show full text]
  • MOL #82305 TITLE PAGE Title: Induced CYP3A4 Expression In
    Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 28, 2021 1 This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted.
    [Show full text]