DOCSLIB.ORG

Abstract DRAYTON, JOSEPHINE BENTLEY

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Abstract DRAYTON, JOSEPHINE BENTLEY Abstract DRAYTON, JOSEPHINE BENTLEY. Methylated Medium- and Long-Chain Fatty Acids as Novel Sources of Anaplerotic Carbon for Exercising Mice. (Under the direction of Dr. Jack Odle and Dr. Lin Xi.) We hypothesized that methylated fatty acids (e.g. 2-methylpentanoic acid (2MeP), phytanic acid or pristanic acid) would provide a novel source of anaplerotic carbon and thereby enhance fatty acid oxidation, especially under stressed conditions when tricarboxylic acid (TCA) cycle intermediates are depleted. The optimal dose of 2MeP, hexanoic acid (C6) and pristanic acid for increasing in vitro [1-14C]-oleic acid oxidation in liver or skeletal muscle homogenates from fasted mice was determined using incremental doses of 0, 0.25, 0.5, 0.75, or 1.0 mM. The 0.25 mM amount maximally stimulated liver tissue oxidation of 14 14 14 [1- C]-oleate to CO2 and [ C]-acid soluble products (ASP; P < 0.05). Similar incubations of 0.25 mM 2MeP, C6, palmitate, phytanic acid, or pristanic acid or 0.1 mM malate or propionyl-CoA were conducted with liver or skeletal muscle homogenates from exercised or sedentary mice. In vitro oxidation of [1-14C]-oleic acid in liver homogenates with 2MeP 14 14 increased mitochondrial CO2 accumulation (P <0.05), but no change in [ C]-ASP accumulation as compared to C6 (P > 0.05). Phytanic acid treatment increased [14C]-ASP accumulation in liver tissue as compared to palmitate (P < 0.05). Exercise increased [14C] accumulations (P < 0.05). Results were consistent with our hypothesis that methyl-branched fatty acids (2-MeP, phytanic and pristanic acids) provide a novel source of anaplerotic carbon and thereby stimulate in vitro fatty acid oxidation in liver and skeletal muscle tissues. Next, serum concentrations of β-hydroxybutyrate (BHB) were measured in mice at 0, 1, 2 and 4 h after gavaging 0.110 mL (~13 umol/kg body weight) of one of three triglycerides: tri-hexanoate (t-C6), tri-2-methylpentanoate (t-2MeP) or t-C6 + t-2MeP (mixed). Serum concentrations of BHB peaked after one hour; however, the peak from the mixed triglyceride was less than from t-C6 by 49% (2.52 versus 4.927 mM, respectively; P < 0.05). No change in BHB was observed from t-2MeP (P < 0.05). After two hours, BHB levels decreased in the t-C6 and mixed gavaged mice, but were not different from one hour concentrations (P < 0.05). After four hours, mice dosed with t-C6 still experienced elevated BHB levels as compared to t-2MeP (P < 0.05). Consistent with our hypothesis, an oral bolus of t-C6 induced ketogenesis whereas t-2MeP did not. Finally, 47 mice were blocked for body weight and randomly allocated to a basal control diet or the basal diet with an additional 8% soybeanoil, 8% t-2MeP, 8% t-C6 or mixed diet (4% t-C6 + 4% t-2MeP). Over the course of 9 weeks, feed intake and body weights were measured weekly. At the end of the trial, tissue weights and serum were collected. Feed intake was not affected by dietary treatment (P > 0.05). However, by week 3, mice fed t-2MeP experienced decreased body weights (P < 0.05). By week 4, all mice fed medium-chain triglycerides weighed less than soyoil fed mice (P < 0.05). Mice fed t-2MeP had increased liver weights (P < 0.05). Mice fed t-2MeP had elevated fasting blood urea nitrogen, alkaline phosphatase and BHB but decreased triglyceride levels as compared to soyoil or t-C6 fed mice (P < 0.05). Serum albumin and nonesterified fatty acids were decreased in t-2MeP fed mice as compared to soyoil fed mice (P < 0.05). We found that feeding t-2MeP decreased body weight gain, increased liver weight and affected serum metabolite profiles as compared to t-C6 or soyoil feeding (P < 0.05). Overall, these results are consistent with our hypothesis that the anaplerotic structure of methyl-branched fatty acids affects metabolism and produces a unique physiological response. Methylated Medium- and Long-Chain Fatty Acids as Novel Sources of Anaplerotic Carbon for Exercising Mice by Josephine Bentley Drayton A thesis submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Master of Science Animal Science Raleigh, North Carolina 2012 APPROVED BY: ______________________ ______________________ Dr. R. Andrew Shanely Dr. Michael McIntosh ______________________ ______________________ Dr. Jack Odle Dr. Lin Xi Committee Co-Chair Committee Co-Chair Biography Josie is from Baltimore, Maryland. She received a Bachelor of Science degree in Animal Science with an emphasis in companion animals from the University of California, Davis in 2006. While there, she worked in a nutrition lab and became interested in nutritional biochemistry. In 2010, Josie began working towards a Master of Science degree, studying Animal Science and Nutrition under the guidance of Dr. Jack Odle and Dr. Lin Xi. Josie will be pursuing a Doctor of Veterinary Medicine degree at the University of Minnesota in the fall of 2012. ii Acknowledgements Thank you first and foremost to Dr. Jack Odle for all of the guidance, inspiration and patience. I am so thankful you took me on as a student. Two years went by quickly but I know the “Odle-isms” about details, “re-search” and tenacity will be lessons I take with me in my future endeavors. Thank you for this opportunity- you are an outstanding mentor. Thank you to Dr. Lin Xi for the instruction and encouragement. You are always willing to explain and teach, and troubleshoot and laugh. Thank you so much for the many roles you play in the lab- you have made it a fun and an educational experience. Thank you to Dr. Shanley for sharing your wealth of knowledge on mouse exercise. Thank you Dr. Sean Adams for your patience and forgiveness as I first learned my way around the lab- I sincerely appreciate that you believed in me and helped me continue my education in research. Dr. Tina Herfel & Dr. Sheila Jacobi- thank you for welcoming me into the lab and always being there for me. I am fortunate to have had such excellent role models and teachers. Thank you Dr. McIntosh, Bai Xiumei, Ahmad, Ericca & Heerangi. Amir, Emily, Kolberg and Frances- thank you for the support!! Gampie and Grandad- thank you for always believing in me, supporting me and encouraging me to follow my dreams. I would like to acknowledge the Kannapolis Scholars program, supported in part by a fellowship provided by Agriculture and Food Research Initiative Grant no. 2010-65200- 20354 from the USDA National Institute of Food and Agriculture. iii Table of Contents List of Tables .................................................................................................................x List of Figures ............................................................................................................. xii Chapter 1: Literature Review .........................................................................................1 Triglyceride and fatty acid structure .........................................................................1 Lipid digestion and absorption ..................................................................................2 Beta-oxidation ...........................................................................................................5 Regulation of β-oxidation ..........................................................................................6 Peroxisomal fatty acid oxidation ...............................................................................8 Ketogenesis .............................................................................................................10 Measurement of triglyceride and fatty acid metabolism in animal models ............11 Anaplerosis ..............................................................................................................12 Anaplerotic reactions ...............................................................................................14 Differences between rodent and human exercise physiology .................................16 Evaluation of exercise endurance in mice ...............................................................17 Regulation of fuel selection during exercise ...........................................................18 Anaplerotic methyl-branched fatty acids ................................................................20 Toxicological evaluation of medium chain triglycerides ........................................22 Figures .....................................................................................................................25 References ...............................................................................................................36 Chapter II: Methyl-branched fatty acids provide anaplerotic carbon to stimulate in vitro fatty acid oxidation in exercised mice .................................................................43 iv Abstract ...................................................................................................................43 Introduction .............................................................................................................44 Materials & Methods ...............................................................................................47 Experimental design............................................................................................47 Tissue homogenates ............................................................................................47 14 14 Total fatty acid oxidation: collection of CO2 & [ C]-acid soluble products ...49 Oxygen consumption ..........................................................................................51
Load more

Recommended publications
  • Substrate Specificity of Rat Liver Mitochondrial Carnitine Palmitoyl Transferase I: Evidence Against S-Oxidation of Phytanic Acid in Rat Liver Mitochondria
    FEBS 15107 FEBS Letters 359 (1995) 179 183 Substrate specificity of rat liver mitochondrial carnitine palmitoyl transferase I: evidence against s-oxidation of phytanic acid in rat liver mitochondria Harmeet Singh*, Alfred Poulos Department of Chemical Pathology, Women's and Children's Hospital 72 King William Road, North Adelaide, SA 5006, Australia Received 23 December 1994 demonstrated that CPTI activity is reversibly inhibited by Abstract The two branched chain fatty acids pristanic acid malonyl-CoA. Recently, it has been shown that malonyl-CoA (2,6,10,14-tetramethylpentadecanoic acid) and phytanic acid inhibits peroxisomal, microsomal and plasma membrane car- (3,7,11,15-tetramethylhexadecanoic acid) were converted to co- nitine acyl transferases [8,10,13]. Therefore, in order to under- enzyme A thioesters by rat liver mitochondrial outer membranes. However, these branched chain fatty acids could not be converted stand the role of CPTI in fatty acid oxidation, CPTI must be to pristanoyl and phytanoyl carnitines, respectively, by mitochon- separated from other carnitine acyl transferases. In view of the drial outer membranes. As expected, the unbranched long chain difficulties in isolating CPTI in the active state, we decided to fatty acids, stearic acid and palmitic acid, were rapidly converted investigate CPTI activity in highly purified mitochondrial outer to stearoyl and palmitoyl carnitines, respectively, by mitochon- membranes from rat liver. We present evidence that branched drial outer membranes. These observations indicate that the chain fatty acids with ~- or fl-methyl groups are poor substrates branched chain fatty acids could not be transported into mito- for CPTI, suggesting that these branched chain fatty acids chondria.
    [Show full text]
  • Ataxia with Loss of Purkinje Cells in a Mouse Model for Refsum Disease
    Ataxia with loss of Purkinje cells in a mouse model for Refsum disease Sacha Ferdinandussea,1,2, Anna W. M. Zomerb,1, Jasper C. Komena, Christina E. van den Brinkb, Melissa Thanosa, Frank P. T. Hamersc, Ronald J. A. Wandersa,d, Paul T. van der Saagb, Bwee Tien Poll-Thed, and Pedro Britesa Academic Medical Center, Departments of aClinical Chemistry (Laboratory of Genetic Metabolic Diseases) and dPediatrics, Emma’s Children Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; bHubrecht Institute, Royal Netherlands Academy of Arts and Sciences 3584 CT Utrecht, The Netherlands; and cRehabilitation Hospital ‘‘De Hoogstraat’’ Rudolf Magnus Institute of Neuroscience, 3584 CG Utrecht, The Netherlands Edited by P. Borst, The Netherlands Cancer Institute, Amsterdam, The Netherlands, and approved October 3, 2008 (received for review June 23, 2008) Refsum disease is caused by a deficiency of phytanoyl-CoA hy- Clinically, Refsum disease is characterized by cerebellar droxylase (PHYH), the first enzyme of the peroxisomal ␣-oxidation ataxia, polyneuropathy, and progressive retinitis pigmentosa, system, resulting in the accumulation of the branched-chain fatty culminating in blindness, (1, 3). The age of onset of the symptoms acid phytanic acid. The main clinical symptoms are polyneuropathy, can vary from early childhood to the third or fourth decade of cerebellar ataxia, and retinitis pigmentosa. To study the patho- life. No treatment is available for patients with Refsum disease, genesis of Refsum disease, we generated and characterized a Phyh but they benefit from a low phytanic acid diet. Phytanic acid is knockout mouse. We studied the pathological effects of phytanic derived from dietary sources only, specifically from the chloro- acid accumulation in Phyh؊/؊ mice fed a diet supplemented with phyll component phytol.
    [Show full text]
  • Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects
    Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects Barbara C. Paton,* Peter C. Sharp,* Denis I. Crane,‡ and Alf Poulos* *Department of Chemical Pathology, Women’s and Children’s Hospital, North Adelaide, South Australia 5006; and ‡Faculty of Science and Technology, Griffith University, Nathan, Queensland 4111, Australia Abstract phology of peroxisomes in their tissues is accompanied by a series of biochemical abnormalities. Subsequent complemen- Pristanic acid oxidation measurements proved a reliable tation analyses have indicated that the three clinical pheno- tool for assessing complementation in fused heterokaryons types can arise from defects in a single gene (1, 2). In addition, from patients with peroxisomal biogenesis defects. We, in spite of all of these patients sharing the same series of bio- therefore, used this method to determine the complementa- chemical abnormalities, it is now clear that the peroxisomal tion groups of patients with isolated defects in peroxisomal biogenesis disorders, as a group, can result from defects in any ␤-oxidation. The rate of oxidation of pristanic acid was re- of at least 10 genes (2, 3). Recent evidence suggests that three duced in affected cell lines from all of the families with in- of these complementation groups have defects in the import of herited defects in peroxisomal ␤-oxidation, thus excluding peroxisomal matrix proteins via both of the known targeting the possibility of a defective acyl CoA oxidase. Complemen- mechanisms (peroxisomal targeting signals [PTS]1 1 and 2), tation analyses indicated that all of the patients belonged to but that for one of the complementation groups the defect is the same complementation group, which corresponded to restricted to proteins targeted via PTS1 (4).
    [Show full text]
  • LIPID METABOLISM-3 Regulation of Fatty Acid Oxidation
    LIPID METABOLISM-3 Regulation of Fatty Acid Oxidation 1. Carnitine shuttle by which fatty acyl groups are carried from cytosolic fatty acyl–CoA into the mitochondrial matrix is rate limiting for fatty acid oxidation and is an important point of regulation. 2. Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-CoA increases in concentration whenever the body is well supplied with carbohydrate; excess glucose that cannot be oxidized or stored as glycogen is converted in the cytosol into fatty acids for storage as triacylglycerol. The inhibition of CAT I by malonyl-CoA ensures that the oxidation of fatty acids is inhibited whenever the liver is actively making triacylglycerols from excess glucose. Two of the enzymes of β-oxidation are also regulated by metabolites that signal energy sufficiency. 3. When the [NADH]/[NAD+] ratio is high, β- hydroxyacyl-CoA dehydrogenase is inhibited; 4. When acetyl-CoA concentration is high, thiolase is inhibited. 5. During periods of vigorous muscle contraction or during fasting, the fall in [ATP] and the rise in [AMP] activate the AMP-activated protein kinase (AMPK). AMPK phosphorylates several target enzymes, including acetyl-CoA carboxylase (ACC), which catalyzes malonyl-CoA synthesis. Phosphorylation and inhibition of ACC lowers the concentration of malonyl-CoA, relieving the inhibition of acyl–carnitine transport into mitochondria and allowing oxidation to replenish the supply of ATP. MITOCHONDRIA PEROXISOME Respiratory chain Respiratory chain Out of organel To citric acid cycle Out of organel Comparison of mitochondrial and peroxisomal beta-oxidation • Another important difference between mitochondrial and peroxisomal oxidation in mammals is in the specificity for fatty acyl– CoAs; the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26:0) and on branched chain fatty acids such as phytanic acid and pristanic acid.
    [Show full text]
  • Thermal Alteration of Organic Matter in Recent Marine Sediments
    THERMAL ALTERATION OF ORGANIC MATTER IN RECENT MARINE SEDIMENTS II. ISOPRENOIDS 1 R. Ikan 2 , M.J. Baedecker an I.R. Kaplan Department of Geophysics and Planetary Physics University of California Los Angeles, California 90024 (NASA-CR-139195) THERHAL ALTERATION OF N74- 30839' ORGANIC HATTER IN RECENT BARINE SEDIHENTS. 2: ISOPRENOIDS (California Univ.) 45 p r'- CSCL 08J Unclas - G3/13 46340 Reproduced by NATIONAL TECHNICAL INFORMATION SERVICE US Department of Commerce Springfield, VA. 22151 Publication No. 1244: Institute of Geophysics & Planetary Physics University of California, Los Angeles, California 90024 Permanent address: Department of Organic Chemistry, Natural Products Laboratory, Hebrew University Jerusa lern, Israel ABSTRACT A series of isoprenoid compounds were isolated from a heat-treated marine sediment (from Tanner Basin) which were not present in the original sediment. Among the compounds identified were: phytol, dihydrophytol, C,,-isoprenoid ketone, phytanic and pristanic acids, C19 - and Co0 -monoolefines, and the alkanes pristane and phytane. The significance and possible routes leading to these compounds is discussed. 2. INTRODUCTION Ever since Bendoraitis et al. (1962) first isolated pristane (2,6,10,14-tetramethylpentadecane) from crude oil in concentrations equal to 0.5% of the total, there has been considerable discussion on the origin of the -isoprenoid hydrocarbons 'in sediments and in petroleum. The two major isoprenoid hydrocarbons normally detected are pristane and phytane (2,6, 10, 14-tetramethylhexadecane), although Cl8 , C16 and CI5 alkanes are also common in oil shales and crude oil, and in some environments, these become the dominant branched hydrocarbons (Arpino et al. 1972). Bendoraitis et al. (1962) believed that the starting compound was chlorophyll from which the phytyl side chain is cleaved and subsequently oxidized to an acid and finally decarboxylated to the C 19 alkane.
    [Show full text]
  • Phytanic Acid, but Not Pristanic Acid, Mediates the Positive Effects of Phytol Derivatives on Brown Adipocyte Differentiation
    FEBS 25988 FEBS Letters 517 (2002) 83^86 View metadata, citation and similar papers at core.ac.uk brought to you by CORE Phytanic acid, but not pristanic acid, mediates the positiveprovided e¡ects by Elsevier of - Publisher Connector phytol derivatives on brown adipocyte di¡erentiation Agatha Schluter, Marta Giralt, Roser Iglesias, Francesc Villarroyaà Departament de Bioqu|¤mica i Biologia Molecular, Universitat de Barcelona, Avinguda Diagonal 645, E-08028 Barcelona, Spain Received 11 February 2002; accepted 12 March 2002 First published online 25 March 2002 Edited by Jacques Hanoune L-oxidation in a transport pathway that involves peroxisomal Abstract The phytol derivatives phytanic acid and pristanic acid may activate nuclear hormone receptors and influence gene carnitine octanoyl transferase (COT) [3]. expression and cell differentiation. Phytanic acid induces brown Phytanic acid can bind and activate at least two types of adipocyte differentiation. It was determined that brown fat and nuclear hormone receptors, retinoid X receptors (RXR) [4,5] brown adipocytes are sites of high gene expression of phytanoyl- and peroxisome proliferator-activated receptor (PPAR)K [6], CoA hydroxylase, the enzyme required for initiation of with a⁄nities lower than other ligands but in the range of the peroxisomal K-oxidation of phytanic acid. However, the effects physiological levels of this fatty acid in blood. Pristanic acid of phytanic acid were not mediated by its K-oxidation product can also activate PPARK [7]. We have recently reported that pristanic acid, which did not promote brown adipocyte differ- phytanic acid, when added to cell culture medium, is an acti- entiation or stimulate transcription of the uncoupling protein-1 vator of brown adipocyte di¡erentiation and transcription of gene.
    [Show full text]
  • Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal Beta-Oxidation Defects
    Oxidation of pristanic acid in fibroblasts and its application to the diagnosis of peroxisomal beta-oxidation defects. B C Paton, … , D I Crane, A Poulos J Clin Invest. 1996;97(3):681-688. https://doi.org/10.1172/JCI118465. Research Article Pristanic acid oxidation measurements proved a reliable tool for assessing complementation in fused heterokaryons from patients with peroxisomal biogenesis defects. We, therefore, used this method to determine the complementation groups of patients with isolated defects in peroxisomal beta-oxidation. The rate of oxidation of pristanic acid was reduced in affected cell lines from all of the families with inherited defects in peroxisomal beta-oxidation, thus excluding the possibility of a defective acyl CoA oxidase. Complementation analyses indicated that all of the patients belonged to the same complementation group, which corresponded to cell lines with bifunctional protein defects. Phytanic acid oxidation was reduced in fibroblasts from some, but not all, of the patients. Plasma samples were still available from six of the patients. The ratio of pristanic acid to phytanic acid was elevated in all of these samples, as were the levels of saturated very long chain fatty acids (VLCFA). However, the levels of bile acid intermediates, polyenoic VLCFA, and docosahexaenoic acid were abnormal in only some of the samples. Pristanic acid oxidation measurements were helpful in a prenatal assessment for one of the families where previous experience had shown that cellular VLCFA levels were not consistently elevated in affected individuals. Find the latest version: https://jci.me/118465/pdf Oxidation of Pristanic Acid in Fibroblasts and Its Application to the Diagnosis of Peroxisomal ␤-Oxidation Defects Barbara C.
    [Show full text]
  • In Vivo Study of Phytanic Acid &-Oxidation in Classic Refsum's
    003 1-399819213205-0566$03.00/0 PEDIATRIC RESEARCH Val. 32, No. 5, 1992 Copyright 0 1992 International Pediatric Research Foundation, Inc Printed in (I.S. A. In Vivo Study of Phytanic Acid &-Oxidationin Classic Refsum's Disease and Chondrodysplasia Punctata HERMAN J. TEN BRINK, DANIELLE S. M. SCHOR, ROBERT M. KOK, FRANS STELLAARD, JOHANNES KNEER, BWEE TIEN POLL-THE, JEAN-MARIE SAUDUBRAY, AND CORNELIS JAKOBS Department of Pediatrics, Free University Hospital, Amsterclam, The Netherlands [H.J.t.B., D.S.M.S., R.M.K., C.J.J;Kinderklinik, Freie Universitat Berlin, Berlin, Germany[J.K.]; University Children's Hospital, Het Wilhe1)nina Kin~lmieltenhuis,Utrechf, The Netherlands /B.T.P.-T.]; and Clinique Medicale Infantile, H6pital des Enfants Malades, Paris, France [J-M.S.J ABSTRACT. A series of in vivo experiments is described in which [l-'3C]phytanic acid was given as an oral substrate to a healthy subject and two patients showing an impair- ment in phytanic acid degradation, one with Refsum's Phytanic acid (3,7,11,15-tetramethylhexadecanoicacid) is a disease and one with chondrodysplasia punctata. After 20-carbon branched chain fatty acid found only in trace amounts intake of the substrate by the control in a dose of 20 mg/ in healthy human beings. Endogenous de novo biosynthesis of kg body weight, the production of I3CO2 was measured in phytanic acid has not been demonstrated, and its origin appears exhaled breath air and the concomitant formation of la- to be exclusively exogenous. Dietary intake of the compound beled 2-hydroxyphytanic acid and of pristanic acid was itself is the major source of phytanic acid in man, and minor demonstrated by plasma analysis.
    [Show full text]
  • Determining the Reference Intervals of Long-Chain Fatty Acids, Phytanic Acid and Pristanic Acid for Diagnostics of Peroxisome Disorders in Children
    J. Life Sci. Biomed. 6(4): 83-89, July 25, 2016 JLSB © 2016, Scienceline Publication Journal of Life Science and Biomedicine ISSN 2251-9939 Determining the Reference Intervals of Long-Chain Fatty Acids, Phytanic Acid and Pristanic Acid for Diagnostics of Peroxisome Disorders in Children Ilgar Salekhovich Mamedov1, Irina Vyacheslavovna Zolkina2, Pavel Borisovich Glagovsky1, and Vladimir Sergeevich Sukhorukov2 1Russian State Medical University, Ostrovitianov str. 1, Moscow, 117997, Russia 2Science research clinical institute of pediatrics, Taldomskaya str. 2, Moscow, 125412, Russia *Corresponding author's email: [email protected] ABSTRACT: In this paper we are given the following information about the biochemical properties of long- chain fatty acids (LCFA), phytanic acid and pristanic acids and their biological role. This article describes procedure of the analysis of these compounds by gas chromatography-mass spectrometry (GC-MS) from the ORIGINAL ARTICLE ORIGINAL sample preparation step to obtain a specific result. Presented reference values of long chain fatty acids and S225199391 PII: Received Received main biochemical markers of peroxisome disorders (phytanic acid and pristanic acid) in plasma and Accepted examples described of changes of these values in various pathologies, such as hereditary diseases in peroxisomes in children and adult. The complex GC-MS analysis of LCFA, pristanic acid and phytanic acid is 13 1 5 an effective method to identify patients with peroxisome impairment, especially for diagnostics Zellweger Jun Jul 6 . 201 000 syndrome spectrum, rhizomelic chondrodisplasia punctata type 1 and Refsume’s disease. This article is 201 . intended for doctors clinical and laboratory diagnosis, specialists in the field of clinical genetics, pediatric 1 6 6 4 - neurologists, and scientists and audiences.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Microbial Metabolism of the Isoprenoid Alkane Pristane (A-Methylglutarate/4,8,12-Trimethyltridecanoate/Fatty Acid Metabolism)
    Proc. Nat. Acad. Sci. USA Vol. 68, No. 7, pp. 1552-1554, July 1971 Microbial Metabolism of the Isoprenoid Alkane Pristane (a-methylglutarate/4,8,12-trimethyltridecanoate/fatty acid metabolism) E. J. McKENNA* AND R. E. KALLIO* Department of Microbiology, University of Iowa, Iowa City, Iowa Communicated by N. J. Leonard, May 10, 1971 ABSTRACT The "inert" hydrocarbon pristane (2,6,- (TMTD) acids from Antarctic whale oil through North 10,14-tetramethylpentadecane) can be utilized as the sole Atlantic whale oil to seal oil has suggested to Ackman and source of carbon and energy for growth of a coryneform soil isolate. Identification of the metabolites 4,8,12- Hooper (11) a correlation with change in food intake for trimethyltridecanoic acid and a-methylglutaric acid marine mammals from a primarily zooplankton diet through indicates that two pathways of fatty acid metabolism a partial fish diet to an exclusive fish diet. More recently, operate in this bacterial strain. Blumer et al. (12) have isolated three phytol-derived olefinic The widespread use of pristane as a biological marker (the 2,10- and 5,10-diene and the 2,6,10-triene appears to be predicated on its structural similarity to hyrocarbons phytol and its apparent stability, which may be only a analogs of pristane) from marine zooplankton and fishes. reflection of the inability of microorganisms to carry out Since these olefins are not present in ancient sediments and its anaerobic destruction. petroleum, they are considered to be valuable markers for the distinction between marine oil pollution and hydrocarbons Isoprenoid hydrocarbons are ubiquitous natural products.
    [Show full text]