The Molecular Basis of PPAR Function
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The Role of Alpha Oxidation in Lipid Metabolism, 2017
THE ROLE OF ALPHA OXIDATION IN LIPID METABOLISM Benjamin John Jenkins Darwin College Medical Research Council – Human Nutrition Research Department of Biochemistry University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy July 2018 DECLARATION This dissertation is the result of my own work and includes nothing, which is the outcome of work done in collaboration except as declared in the preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. In accordance with the University of Cambridge guidelines, this thesis does not exceed 60,000 words. Signed: ______________________________________________________________ Date: _______________________________________________________________ Benjamin John Jenkins BSc. MSc. Darwin College, Silver Street, Cambridge, CB3 9EU by i 2014 Word Template Template Friedman Friedman & Morgan Morgan & ii The Role of Alpha Oxidation in Lipid Metabolism, 2017 ABSTRACT Recent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake. -
Adipose Tissue NAPE-PLD Controls Fat Mass Development by Altering the Browning Process and Gut Microbiota
ARTICLE Received 11 Jul 2014 | Accepted 4 Feb 2015 | Published 11 Mar 2015 DOI: 10.1038/ncomms7495 OPEN Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota Lucie Geurts1, Amandine Everard1,*, Matthias Van Hul1,*, Ahmed Essaghir2, Thibaut Duparc1, Se´bastien Matamoros1, Hubert Plovier1, Julien Castel3, Raphael G.P. Denis3, Marie Bergiers1, Ce´line Druart1, Mireille Alhouayek4, Nathalie M. Delzenne1, Giulio G. Muccioli4, Jean-Baptiste Demoulin2, Serge Luquet3 & Patrice D. Cani1 Obesity is a pandemic disease associated with many metabolic alterations and involves several organs and systems. The endocannabinoid system (ECS) appears to be a key regulator of energy homeostasis and metabolism. Here we show that specific deletion of the ECS synthesizing enzyme, NAPE-PLD, in adipocytes induces obesity, glucose intolerance, adipose tissue inflammation and altered lipid metabolism. We report that Napepld-deleted mice present an altered browning programme and are less responsive to cold-induced browning, highlighting the essential role of NAPE-PLD in regulating energy homeostasis and metabolism in the physiological state. Our results indicate that these alterations are mediated by a shift in gut microbiota composition that can partially transfer the phenotype to germ-free mice. Together, our findings uncover a role of adipose tissue NAPE-PLD on whole-body metabolism and provide support for targeting NAPE-PLD-derived bioactive lipids to treat obesity and related metabolic disorders. 1 Metabolism and Nutrition Research Group, WELBIO-Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Universite´ catholique de Louvain, Avenue E. Mounier, 73 B1.73.11, 1200 Brussels, Belgium. 2 de Duve Institute, Universite´ catholique de Louvain, Avenue Hippocrate, 74 B1.74.05, 1200 Brussels, Belgium. -
Downloaded As a Text File, Is Completely Dynamic
BMC Bioinformatics BioMed Central Database Open Access ORENZA: a web resource for studying ORphan ENZyme activities Olivier Lespinet and Bernard Labedan* Address: Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris-Sud, Bâtiment 400, 91405 Orsay Cedex, France Email: Olivier Lespinet - [email protected]; Bernard Labedan* - [email protected] * Corresponding author Published: 06 October 2006 Received: 25 July 2006 Accepted: 06 October 2006 BMC Bioinformatics 2006, 7:436 doi:10.1186/1471-2105-7-436 This article is available from: http://www.biomedcentral.com/1471-2105/7/436 © 2006 Lespinet and Labedan; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Despite the current availability of several hundreds of thousands of amino acid sequences, more than 36% of the enzyme activities (EC numbers) defined by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) are not associated with any amino acid sequence in major public databases. This wide gap separating knowledge of biochemical function and sequence information is found for nearly all classes of enzymes. Thus, there is an urgent need to explore these sequence-less EC numbers, in order to progressively close this gap. Description: We designed ORENZA, a PostgreSQL database of ORphan ENZyme Activities, to collate information about the EC numbers defined by the NC-IUBMB with specific emphasis on orphan enzyme activities. -
Fatty Acid Oxidation
FATTY ACID OXIDATION 1 FATTY ACIDS A fatty acid contains a long hydrocarbon chain and a terminal carboxylate group. The hydrocarbon chain may be saturated (with no double bond) or may be unsaturated (containing double bond). Fatty acids can be obtained from- Diet Adipolysis De novo synthesis 2 FUNCTIONS OF FATTY ACIDS Fatty acids have four major physiological roles. 1)Fatty acids are building blocks of phospholipids and glycolipids. 2)Many proteins are modified by the covalent attachment of fatty acids, which target them to membrane locations 3)Fatty acids are fuel molecules. They are stored as triacylglycerols. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs of a cell or organism. 4)Fatty acid derivatives serve as hormones and intracellular messengers e.g. steroids, sex hormones and prostaglandins. 3 TRIGLYCERIDES Triglycerides are a highly concentrated stores of energy because they are reduced and anhydrous. The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1) Triacylglycerols are nonpolar, and are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly 4 TRIGLYCERIDES V/S GLYCOGEN A gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir. The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the Triacylglycerol stores allow survival for several weeks. 5 PROVISION OF DIETARY FATTY ACIDS Most lipids are ingested in the form of triacylglycerols, that must be degraded to fatty acids for absorption across the intestinal epithelium. -
Manual D'estil Per a Les Ciències De Laboratori Clínic
MANUAL D’ESTIL PER A LES CIÈNCIES DE LABORATORI CLÍNIC Segona edició Preparada per: XAVIER FUENTES I ARDERIU JAUME MIRÓ I BALAGUÉ JOAN NICOLAU I COSTA Barcelona, 14 d’octubre de 2011 1 Índex Pròleg Introducció 1 Criteris generals de redacció 1.1 Llenguatge no discriminatori per raó de sexe 1.2 Llenguatge no discriminatori per raó de titulació o d’àmbit professional 1.3 Llenguatge no discriminatori per raó d'ètnia 2 Criteris gramaticals 2.1 Criteris sintàctics 2.1.1 Les conjuncions 2.2 Criteris morfològics 2.2.1 Els articles 2.2.2 Els pronoms 2.2.3 Els noms comuns 2.2.4 Els noms propis 2.2.4.1 Els antropònims 2.2.4.2 Els noms de les espècies biològiques 2.2.4.3 Els topònims 2.2.4.4 Les marques registrades i els noms comercials 2.2.5 Els adjectius 2.2.6 El nombre 2.2.7 El gènere 2.2.8 Els verbs 2.2.8.1 Les formes perifràstiques 2.2.8.2 L’ús dels infinitius ser i ésser 2.2.8.3 Els verbs fer, realitzar i efectuar 2.2.8.4 Les formes i l’ús del gerundi 2.2.8.5 L'ús del verb haver 2.2.8.6 Els verbs haver i caldre 2.2.8.7 La forma es i se davant dels verbs 2.2.9 Els adverbis 2.2.10 Les locucions 2.2.11 Les preposicions 2.2.12 Els prefixos 2.2.13 Els sufixos 2.2.14 Els signes de puntuació i altres signes ortogràfics auxiliars 2.2.14.1 La coma 2.2.14.2 El punt i coma 2.2.14.3 El punt 2.2.14.4 Els dos punts 2.2.14.5 Els punts suspensius 2.2.14.6 El guionet 2.2.14.7 El guió 2.2.14.8 El punt i guió 2.2.14.9 L’apòstrof 2.2.14.10 L’interrogant 2 2.2.14.11 L’exclamació 2.2.14.12 Les cometes 2.2.14.13 Els parèntesis 2.2.14.14 Els claudàtors 2.2.14.15 -
Integrated Physiology and Systems Biology of Ppara
Review Integrated physiology and systems biology of PPARa Sander Kersten* ABSTRACT The Peroxisome Proliferator Activated Receptor alpha (PPARa) is a transcription factor that plays a major role in metabolic regulation. This review addresses the functional role of PPARa in intermediary metabolism and provides a detailed overview of metabolic genes targeted by PPARa, with a focus on liver. A distinction is made between the impact of PPARa on metabolism upon physiological, pharmacological, and nutritional activation. Low and high throughput gene expression analyses have allowed the creation of a comprehensive map illustrating the role of PPARa as master regulator of lipid metabolism via regulation of numerous genes. The map puts PPARa at the center of a regulatory hub impacting fatty acid uptake, fatty acid activation, intracellular fatty acid binding, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, lipid droplet biology, gluconeogenesis, and bile synthesis/secretion. In addition, PPARa governs the expression of several secreted proteins that exert local and endocrine functions. Ó 2014 The Author. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/). Keywords PPARa; Liver; Transcriptional networks; Lipid metabolism; Expression profiling; Metabolic homeostasis; Systems biology 1. INTRODUCTION deacetylase and histone acetyltransferase activity, respectively, necessary for the assembly of the transcription initiation complex [10]. PPARa was the first member to be cloned of a small subfamily of Readers are referred to another review for more detailed information nuclear receptors called Peroxisome Proliferators Activated Receptors on co-activators in PPAR-dependent gene regulation [11]. -
Fatty Acid Oxidation- Notes
Fatty acid oxidation- Notes See how fatty acids are broken down and used to generate ATP . Fatty acids provide highly efficient energy storage, delivering more energy per gram than carbohydrates like glucose. In tissues with high energy requirement, such as heart, up to 50– 70% of energy, in the form of ATP production, comes from fatty acid (FA) beta-oxidation. During fatty acid β-oxidation long chain acyl-CoA molecules – the main components of FAs – are broken to acetyl-CoA molecules. Fatty acid transport into mitochondria Fatty acids are activated for degradation by conjugation with coenzyme A (CoA) in the cytosol. The long-chain fatty-acyl-CoA is then modified by carnitine palmitoyltransferase 1 (CPT1) to acylcarnitine and transported across the inner mitochondrial membrane by carnitine translocase (CAT). CPT2 then coverts the long chain acylcarnitine back to long- chain acyl-CoA before beta-oxidation. Breakdown of fats yields fatty acids and glycerol. Glycerol can be readily converted to DHAP for oxidation in glycolysis or synthesis into glucose in gluconeogenesis. Fatty acids are broken down in two carbon units of acetyl-CoA. To be oxidized, they must be transported through the cytoplasm attached to coenzyme A and moved into mitochondria. The latter step requires removal of the CoA and attachment of the fatty acid to a molecule of carnitine. The carnitine complex is transported across the inner membrane of the mitochondrion after which the fatty acid is reattached to coenzyme A in the mitochondrial matrix. Dr Anjali Saxena Page 1 Figure- Movement of Acyl-CoAs into the Mitochondrial Matrix The process of fatty acid oxidation, called beta oxidation, is fairly simple. -
Phytosphingosine Degradation Pathway Includes Fatty Acid Α
Phytosphingosine degradation pathway includes PNAS PLUS fatty acid α-oxidation reactions in the endoplasmic reticulum Takuya Kitamuraa, Naoya Sekia, and Akio Kiharaa,1 aLaboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 21, 2017 (received for review January 4, 2017) Although normal fatty acids (FAs) are degraded via β-oxidation, sphingolipids, especially galactosylceramide and its sulfated de- unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched rivative sulfatide, contain a 2-OH FA (13, 15, 16). Their 2-OH FAs are degraded via α-oxidation. Phytosphingosine (PHS) is one groups are important for the formation and maintenance of the of the long-chain bases (the sphingolipid components) and exists myelin sheath, which is composed of a multilayered lipid structure, in specific tissues, including the epidermis and small intestine in probably by enhancing lipid–lipid interactions via hydrogen bonds. mammals. In the degradation pathway, PHS is converted to 2-OH The FA 2-hydroxylase FA2H catalyzes conversion of FAs to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA FAs (12, 17). Reflecting the importance of the 2-OH groups of α-oxidation. However, the detailed reactions and genes involved galactosylceramide and sulfatide in myelin, FA2H mutations cause in the α-oxidation reactions of the PHS degradation pathway have hereditary spastic paraplegia in human (18, 19) and late-onset axon yet to be determined. In the present study, we reveal the entire and myelin sheath degeneration in mice (16, 20). -
A Review of Odd-Chain Fatty Acid Metabolism and the Role of Pentadecanoic Acid (C15:0) and Heptadecanoic Acid (C17:0) in Health and Disease
Molecules 2015, 20, 2425-2444; doi:10.3390/molecules20022425 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review A Review of Odd-Chain Fatty Acid Metabolism and the Role of Pentadecanoic Acid (C15:0) and Heptadecanoic Acid (C17:0) in Health and Disease Benjamin Jenkins, James A. West and Albert Koulman * MRC HNR, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK; E-Mails: [email protected] (B.J.); [email protected] (J.A.W.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +44-(0)-1223-426-356. Academic Editor: Derek J. McPhee Received: 11 December 2014 / Accepted: 23 January 2015 / Published: 30 January 2015 Abstract: The role of C17:0 and C15:0 in human health has recently been reinforced following a number of important biological and nutritional observations. Historically, odd chain saturated fatty acids (OCS-FAs) were used as internal standards in GC-MS methods of total fatty acids and LC-MS methods of intact lipids, as it was thought their concentrations were insignificant in humans. However, it has been thought that increased consumption of dairy products has an association with an increase in blood plasma OCS-FAs. However, there is currently no direct evidence but rather a casual association through epidemiology studies. Furthermore, a number of studies on cardiometabolic diseases have shown that plasma concentrations of OCS-FAs are associated with lower disease risk, although the mechanism responsible for this is debated. One possible mechanism for the endogenous production of OCS-FAs is α-oxidation, involving the activation, then hydroxylation of the α-carbon, followed by the removal of the terminal carboxyl group. -
A Role for the Peroxisomal 3-Ketoacyl-Coa Thiolase B Enzyme in the Control of Pparα-Mediated Upregulation of SREBP-2 Target Genes in the Liver
A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα-mediated upregulation of SREBP-2 target genes in the liver. Marco Fidaleo, Ségolène Arnauld, Marie-Claude Clémencet, Grégory Chevillard, Marie-Charlotte Royer, Melina de Bruycker, Ronald Wanders, Anne Athias, Joseph Gresti, Pierre Clouet, et al. To cite this version: Marco Fidaleo, Ségolène Arnauld, Marie-Claude Clémencet, Grégory Chevillard, Marie-Charlotte Royer, et al.. A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα- mediated upregulation of SREBP-2 target genes in the liver.: ThB and cholesterol biosynthesis in the liver. Biochimie, Elsevier, 2011, 93 (5), pp.876-91. 10.1016/j.biochi.2011.02.001. inserm-00573373 HAL Id: inserm-00573373 https://www.hal.inserm.fr/inserm-00573373 Submitted on 3 Mar 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Fidaleo et al ., ThB and genes of cholesterol biosynthesis in liver 1 A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of 2 PPAR ααα-mediated upregulation of SREBP-2 target genes in the liver 3 Marco Fidaleo 1,2,8# , Ségolène Arnauld 1,2# , Marie-Claude Clémencet 1,2 , Grégory Chevillard 1,2,9 , 4 Marie-Charlotte Royer 1,2 , Melina De Bruycker 3, Ronald J.A. -
12) United States Patent (10
US007635572B2 (12) UnitedO States Patent (10) Patent No.: US 7,635,572 B2 Zhou et al. (45) Date of Patent: Dec. 22, 2009 (54) METHODS FOR CONDUCTING ASSAYS FOR 5,506,121 A 4/1996 Skerra et al. ENZYME ACTIVITY ON PROTEIN 5,510,270 A 4/1996 Fodor et al. MICROARRAYS 5,512,492 A 4/1996 Herron et al. 5,516,635 A 5/1996 Ekins et al. (75) Inventors: Fang X. Zhou, New Haven, CT (US); 5,532,128 A 7/1996 Eggers Barry Schweitzer, Cheshire, CT (US) 5,538,897 A 7/1996 Yates, III et al. s s 5,541,070 A 7/1996 Kauvar (73) Assignee: Life Technologies Corporation, .. S.E. al Carlsbad, CA (US) 5,585,069 A 12/1996 Zanzucchi et al. 5,585,639 A 12/1996 Dorsel et al. (*) Notice: Subject to any disclaimer, the term of this 5,593,838 A 1/1997 Zanzucchi et al. patent is extended or adjusted under 35 5,605,662 A 2f1997 Heller et al. U.S.C. 154(b) by 0 days. 5,620,850 A 4/1997 Bamdad et al. 5,624,711 A 4/1997 Sundberg et al. (21) Appl. No.: 10/865,431 5,627,369 A 5/1997 Vestal et al. 5,629,213 A 5/1997 Kornguth et al. (22) Filed: Jun. 9, 2004 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2005/O118665 A1 Jun. 2, 2005 EP 596421 10, 1993 EP 0619321 12/1994 (51) Int. Cl. EP O664452 7, 1995 CI2O 1/50 (2006.01) EP O818467 1, 1998 (52) U.S. -
Details About Three Fatty Acid Oxidation Pathways Occurring in Man
Supplement information Details about three fatty acid oxidation pathways occurring in man Alpha oxidation Definition: Oxidation of the alpha carbon of the fatty acid, chain shortened by 1 carbon atom. Localization: Peroxisomes1 Substrates: Phytanic acid, 3-methyl fatty acids and their alcohol and aldehyde derivatives, metabolites of farnesol, geranylgeraniol, and dolichols2, 3. Steps in the pathway: Activation requires ATP and CoA. Hydroxylation requires iron, ascorbate and alpha-keto-glutarate as cofactors and secondary substrates. Lysis requires thymine pyrophosphate and magnesium ions. Dehydrogenation requires NADP. End products are transported into mitochondria for further oxidation. Enzymes and genes involved: Very long-chain acyl-CoA synthetase (E.C. 6.2.1.-) (SLC27A2, GeneID: 11001)4, phytanoyl-CoA dioxygenase (E.C. 1.14.11.18, PHYH, GeneID: 5264), 2-hydrosyphytanoyl-coA lyase (E.C. 4.1.-.-, HACL1, GeneID: 26061), and aldehyde dehydrogenase (E.C. 1.2.1.3, ALDH3A2, GeneID: 224). Disorders associated: Zellweger syndrome including RCDP type 1, where PTS2 receptor is defective and PHYH is unable to enter peroxisomes, and Refsum’s disease. Special features/ purpose: At the sub cellular level, the activation step can occur in the mitochondrion, endoplasmic reticulum, and peroxisome. Formic acid is the main byproduct of this pathway as opposed to carbon dioxide. Phytanic acid usually undergoes alpha oxidation; however, under conditions of enzyme deficiency, it undergoes omega oxidation and 3- methyladipic acid is produced as the end product5. Omega oxidation Definition: Oxidation of omega carbon of the fatty acid for generation of mono- and di- carboxylic acids. No chain shortening occurs. Localization: Fatty acid shuttles between cytosol and microsomes before entering the peroxisomes6.