DOCSLIB.ORG

Inhibition of the Oxygen Sensor PHD2 in the Liver Improves Survival in Lactic Acidosis by Activating the Cori Cycle

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inhibition of the Oxygen Sensor PHD2 in the Liver Improves Survival in Lactic Acidosis by Activating the Cori Cycle Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle Tomohiro Suharaa,b,1, Takako Hishikia,c,d,e,1, Masataka Kasaharaa,f,1, Noriyo Hayakawaa,c,d, Tomoko Oyaizua,b, Tsuyoshi Nakanishia,g, Akiko Kuboa,d, Hiroshi Morisakib, William G. Kaelin Jr.h,i,2, Makoto Suematsua,d,2, and Yoji Andrew Minamishimaa,d,2 aDepartment of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; bDepartment of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan; cTranslational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan; dJapan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; eJapan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; fDepartment of Pharmacology, Tokyo Dental College, Tokyo 101-0061, Japan; gMS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan; hDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215; and iHoward Hughes Medical Institute, Chevy Chase, MD 20815 Contributed by William G. Kaelin, Jr., August 12, 2015 (sent for review June 22, 2015; reviewed by Ralph J. DeBerardinis) Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible Results and Discussion factor-dependent hypoxic response, including anaerobic glycolysis, Inactivation of Phd2 in the Liver Reduces the Blood Lactate Level. which causes large amounts of lactate to be released from cells into PHD2 is the dominant HIF-prolyl hydroxylase in vivo among all the circulation. We found that Phd2-null mouse embryonic fibroblasts three PHDs (4), and inactivating PHD2 alone is sufficient to ac- (MEFs) produced more lactate than wild-type MEFs, as expected, tivate HIF (5), which would enhance lactate efflux from the cells. − − whereas systemic inactivation of PHD2 in mice did not cause hyper- As expected, lactate efflux from Phd2 / mouse embryonic fibro- + + lacticacidemia. This unexpected observation led us to hypothesize blasts (MEFs) was significantly higher than from Phd2 / MEFs that the hypoxic response activated in the liver enhances the Cori (Fig. 1A). We therefore expected that systemic inactivation of – cycle, a lactate glucose carbon recycling system between muscle PHD2 would cause increased lactic acid production and hyper- and liver, and thereby decreases circulating lactate. Consistent with lacticacidemia. To test this, we studied mice in which Phd2 can be this hypothesis, blood lactate levels measured after a treadmill or conditionally inactivated systemically (Phd2-SKO) (5). We first Phd2 lactate tolerance test were significantly lower in -liver-specific confirmed that the expression levels of some mRNAs linked to Phd2-LKO 13 knockout ( ) mice than in control mice. An in vivo C-labeled glycolysis were significantly increased in skeletal muscles of Phd2- lactate incorporation assay revealed that the livers of Phd2-LKO mice 13 SKO mice compared to control mice (Fig. S1A and Table S1). produce significantly more glucose derived from C-labeled lactate Unexpectedly, however, blood lactate levels in Phd2-SKO were than control mice, suggesting that blockade of PHD2 in the liver ame- not higher, and in fact tended to be lower, than in the control liorates lactic acidosis by activating gluconeogenesis from lactate. Phd2 LKO mice, although this difference did not reach statistical significance - mice were resistant to lactic acidosis induced by injection (Fig. 1B). To examine the mechanisms responsible for this un- of a lethal dose of lactate, displaying a significant elongation of sur- expected observation, we measured lactate levels in mice sub- vival. Moreover, oral administration of a PHD inhibitor improved sur- jected to treadmill exercise. Blood lactate levels were significantly vival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in Significance some critically ill patients. When oxygen availability becomes limited, organs and cells ac- hypoxic response | PHD inhibitor | hyperlactatemia | gluconeogenesis | tivate the hypoxic response to generate energy. This response sepsis releases a large amount of lactate into the circulation as a result of anaerobic glycolysis. However, we found that activating the hypoxic response in the liver by inhibiting the oxygen sensor n metazoans, the cellular enzyme lactate dehydrogenase (LDH) prolyl hydroxylase domain-containing protein 2 (PHD2) en- converts pyruvate to lactate, which is then exported from cells. I hances the uptake of lactate for gluconeogenesis, also known as Lactate efflux is increased under hypoxic conditions, where avail- the Cori cycle, and ameliorates lactic acidosis. Our findings sug- able molecular oxygen is limited. The cellular response to hypoxia is gest that PHD2 serves as a viable drug target for the treat- mainly regulated by the heterodimeric transcription factor hypoxia- ment of life-threatening lactic acidosis, which is frequent inducible factor (HIF), which consists of an unstable alpha subunit complication of severe infectious and ischemic diseases, as well α β (HIF ) and a stable beta subunit (HIF ) (1, 2). HIF prolyl hy- as of biguanide treatment in patients with diabetes with droxylases called PHDs (PHD1–PHD3) (3) target HIFα for ubiq- renal failure. uitin-proteasome-dependent protein degradation under normoxic conditions, lowering HIF levels and suppressing HIF signaling. Author contributions: T.S., T.H., M.K., W.G.K., M.S., and Y.A.M. designed research; T.S., Under hypoxic conditions, PHDs become inactive because they re- T.H., M.K., N.H., T.O., W.G.K., M.S., and Y.A.M. performed research; T.S., T.H., M.K., W.G.K., M.S., and Y.A.M. analyzed data; and T.S., T.H., M.K., T.N., A.K., H.M., W.G.K., M.S., and Y.A.M. quire molecular oxygen for enzymatic activity. This inactivation leads wrote the paper. α to HIF stabilization and activation of HIF signaling. Activated HIF Reviewers included: R.J.D., University of Texas-Southwestern Medical Center. up-regulates genes involved in various events, including erythro- The authors declare no conflict of interest. cytosis, neovascularization, and anaerobic glycolysis. HIF activation 1T.S., T.H., and M.K. contributed equally to this work. enhances anaerobic glycolysis by up-regulating glucose trans- 2To whom correspondence may be addressed. Email: [email protected], porters and glycolytic enzymes, including lactate dehydro- [email protected], or [email protected]. genase A (LDHA), and monocarboxylate transporters, leading This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. to enhanced lactate secretion. 1073/pnas.1515872112/-/DCSupplemental. 11642–11647 | PNAS | September 15, 2015 | vol. 112 | no. 37 www.pnas.org/cgi/doi/10.1073/pnas.1515872112 Downloaded by guest on October 1, 2021 ABC D E p=0.000548 p=2.19x10-19 0.9 p=0.00101 9 9 5 5 p=0.891 0.15 0.8 8 8 4 4 0.7 7 7 p=0.325 0.6 6 6 0.10 3 3 0.5 5 p=0.248 5 0.4 4 4 2 2 0.3 3 3 0.05 0.2 2 2 1 1 Phd2/Actb 0.1 1 1 0 Blood lactate level (mM) 0 Blood lactate level (mM) 0 0 0 0 +/+ -/- Urinary lactate level (mM) Urinary lactate level (mM) Lactate efflux (pmol/h/cell) Phd2 Phd2 Control (n=3) Control (n=3) 0 min 20 min Control (n=7) MEFs MEFs Phd2-SKO (n=3) Phd2-SKO (n=3) Control (n=3) Phd2-SKO (n=3) Phd2-LKO (n=8) FG H p=0.00202 p=0.0396 7 7 80 6 6 10 9 200 p=0.0000253 5 5 70 (mM) 8 4 4 7 150 p=0.405 3 3 60 6 5 * † 2 2 100 50 4 ‡ 1 1 3 Control (n=8) § 50 0 0 40 2 Blood lactate level (mM) Blood lactate level (mM) Phd2-LKO (n=7) Time to exhaustion (min) 1 Control Phd2-LKO 0 Control (n=11) Control (n=11) Blood lactate level 0 (n=11) (n=12) 0 5 10 15 20 Control Phd2-LKO Phd2-LKO (n=12) Phd2-LKO (n=12) Time (min) Blood lactate AUC (mM x min) (n=8) (n=7) + + − − Fig. 1. Inactivation of Phd2 in the liver reduces blood lactate levels. (A) Lactate efflux analysis in Phd2 / and Phd2 / MEFs. Values were from triplicated dishes. Error bars indicate 1 SEM. (B) The blood lactate level in Control and Phd2-SKO mice. Error bars, SEM. (C) The blood lactate level 50 min after the treadmill in Control and Phd2-SKO mice. Error bars, SEM. (D) Urinary lactate measurement. Lactate levels in urine were measured before (Left) and 20 min after (Right) the lactate injection in Control and Phd2-SKO mice. Error bars, SEM. (E) Real-time RT-PCR analysis of Phd2 mRNA in the livers of Control and Phd2-LKO mice. Error bars, SEM. (F) Blood lactate levels in Control and Phd2-LKO mice. Error bars, SEM. (G) Treadmill experiment in Control and Phd2-LKO mice. The blood lactate levels 50 min after the exercise (Left) and time to exhaustion (Right) are shown. Error bars, SEM. (H) Lactate tolerance test. 0.5 mg per gram body weight of lactate was intraperitoneally injected, and the blood lactate levels were measured at the indicated time (Left). Area under the curve (AUC) was also analyzed (Right). Error bars, SEM. *P = 0.0448; †P = 0.000342; ‡P = 0.000118; §P = 2.53 × 10−7 versus Control. lower in Phd2-SKO mice after treadmill exercise compared to in the Phd2-LKO mice after 50 min of treadmill exercise were control mice (Fig.
Load more

Recommended publications
  • Hungry for Your Alanine: When Liver Depends on Muscle Proteolysis
    The Journal of Clinical Investigation COMMENTARY Hungry for your alanine: when liver depends on muscle proteolysis Theresia Sarabhai1,2 and Michael Roden1,2,3 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany. 2German Center for Diabetes Research, München-Neuherberg, Germany. 3Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. β-oxidation and the acetyl-CoA pool, which Fasting requires complex endocrine and metabolic interorgan crosstalk, allosterically activates pyruvate carboxylase flux (V ), and which, together with glycerol which involves shifting from glucose to fatty acid oxidation, derived from PC adipose tissue lipolysis, in order to preserve glucose for the brain. The as substrate, maintains the rates of hepatic gluconeogenesis and endogenous glucose glucose-alanine (Cahill) cycle is critical for regenerating glucose. In this issue production (V ) (8). of JCI, Petersen et al. report on their use of an innovative stable isotope EGP tracer method to show that skeletal muscle–derived alanine becomes rate Liver–skeletal muscle controlling for hepatic mitochondrial oxidation and, in turn, for glucose metabolic crosstalk production during prolonged fasting. These results provide new insight Other metabolic pathways are also known into skeletal muscle–liver metabolic crosstalk during the fed-to-fasting to connect skeletal muscle and liver. The transition in humans. Cori
    [Show full text]
  • Thèse De Doctorat
    THÈSE DE DOCTORAT Rôle des microARNs et de leur machinerie dans les hépatocytes et les cellules béta pancréatiques Role of microRNAs and their machinery in hepatocytes and pancreatic beta cells Gaia FABRIS IRCAN CNRS UMR 7284 – INSERM U1081 Présentée en vue de l’obtention Devant le jury, composé de : du grade de docteur en Sciences Francesco Beguinot, Professeur d’Université Côte d’Azur d’Endocrinologie, Università di Napoli Mention : interactions moléculaires et Federico II cellulaires Giulia Chinetti, Professeure de Biochimie, Dirigée par : Giulia Chinetti UCA Nice Co-encadrée par : Patricia Lebrun Magalie Ravier, CRCN, Inserm, IGF Soutenue le : 7 Juin 2019 Montpellier Emmanuel Van Obberghen, Professeur de Biochimie, UCA Nice Rôle des microARNs et de leur machinerie dans les hépatocytes et les cellules béta pancréatiques Jury : Président de jury Emmanuel Van Obberghen, Professeur de Biochimie, UCA Nice Rapporteurs Faeso Beguiot, Pofesseu d’Endocrinologie, Département de Médecine translationnelle Université de Naples Federico II, Italie Magalie Ravier, CRCN, Inserm, Institut de Génomique Fonctionnelle Montpellier, France Résumé Das le foie oal de l’adulte les hpatotes sot das u tat de uiesee, sauf los d’ue situatio d’agessio phsiue ou toique. Dans ces cas-là, afin de pouvoir aitei leu ôle das l’hoostasie de l’ogaise les hpatotes edoags ou sauvegardés vont proliférer. Un des facteurs limitants pour la prolifération est la psee d’aides ais, ui sot essaies pour la synthèse des protéines au cours de la polifatio et diisio ellulaie, et pou l’atiatio de la oie TOR, ui joue un rôle clef dans la régulation de la prolifération cellulaire.
    [Show full text]
  • Hepatocyte Specific Expression of an Oncogenic Variant of Β-Catenin Results in Lethal Metabolic Dysfunction in Mice
    www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 13), pp: 11243-11257 Research Paper Hepatocyte specific expression of an oncogenic variant of β-catenin results in lethal metabolic dysfunction in mice Ursula J. Lemberger1,2, Claudia D. Fuchs2, Christian Schöfer3, Andrea Bileck4, Christopher Gerner4, Tatjana Stojakovic5, Makoto M. Taketo6, Michael Trauner2, Gerda Egger1,7 and Christoph H. Österreicher8 1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 2Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria 3Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria 4Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria 5Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 6Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan 7Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria 8Institute of Pharmacology, Medical University Vienna, Vienna, Austria Correspondence to: Ursula J. Lemberger, email: [email protected], [email protected] Keywords: Wnt signaling pathway; liver cancer; lipid metabolism; glucose metabolism; mitochondrial disorder Received: August 31, 2017 Accepted: January 25, 2018 Published: January 30, 2018 Copyright: Lemberger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Wnt/β-catenin signaling plays a crucial role in embryogenesis, tissue homeostasis, metabolism and malignant transformation of different organs including the liver. Continuous β-catenin signaling due to somatic mutations in exon 3 of the Ctnnb1 gene is associated with different liver diseases including cancer and cholestasis.
    [Show full text]
  • The Impact of Acute Thermal Stress on the Metabolome of the Black Rockfish (Sebastes Schlegelii)
    RESEARCH ARTICLE The impact of acute thermal stress on the metabolome of the black rockfish (Sebastes schlegelii) 1☯³ 1☯³ 1 1 1 1 Min SongID , Ji Zhao , Hai-Shen Wen *, Yun Li *, Ji-Fang Li , Lan-Min Li , Ya- Xiong Tao2 1 Key Laboratory of Mariculture (Ocean University of China), Ministry of Education, Ocean University of China, Qingdao, P. R. China, 2 Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America a1111111111 ☯ These authors contributed equally to this work. a1111111111 ³ These authors are co-first authors on this work. a1111111111 * [email protected] (HSW); [email protected] (YL) a1111111111 a1111111111 Abstract Acute change in water temperature causes heavy economic losses in the aquaculture industry. The present study investigated the metabolic and molecular effects of acute ther- OPEN ACCESS mal stress on black rockfish (Sebastes schlegelii). Gas chromatography time-of-flight mass Citation: Song M, Zhao J, Wen H-S, Li Y, Li J-F, Li spectrometry (GC-TOF-MS)-based metabolomics was used to investigate the global meta- L-M, et al. (2019) The impact of acute thermal stress on the metabolome of the black rockfish bolic response of black rockfish at a high water temperature (27ÊC), low water temperature (Sebastes schlegelii). PLoS ONE 14(5): e0217133. (5ÊC) and normal water temperature (16ÊC). Metabolites involved in energy metabolism and https://doi.org/10.1371/journal.pone.0217133 basic amino acids were significantly increased upon acute exposure to 27ÊC (P < 0.05), and Editor: Jose L. Soengas, Universidade de Vigo, no change in metabolite levels occurred in the low water temperature group.
    [Show full text]
  • Part 2 Biochemistry of Hormones. Metabolism of Carbohydrates and Lipids Частина 2 Біохімія Гормонів. О
    МІНІСТЕРСТВО ОХОРОНИ ЗДОРОВ'Я УКРАЇНИ Харківський національний медичний університет PART 2 BIOCHEMISTRY OF HORMONES. METABOLISM OF CARBOHYDRATES AND LIPIDS Self-Study Guide for Students of General Medicine Faculty in Biochemistry ЧАСТИНА 2 БІОХІМІЯ ГОРМОНІВ. ОБМІН ВУГЛЕВОДІВ ТА ЛІПІДІВ Методичні вказівки для підготовки до практичних занять з біологічної хімії (для студентів медичних факультетів) Затверджено вченою Радою ХНМУ Протокол № 12 від 20.10.2016 р. Харків ХНМУ 2016 Self-study guide for students of general medicine faculty in biochemistry. Part 2: Biochemistry of hormones. Metabolism of carbohydrates and lipids / Comp.: O. Nakonechna, S. Stetsenko, L. Popova, A. Tkachenko. et al. – Kharkiv: KhNMU, 2016. – 84 p. Covpilers: Nakonechna O. Stetsenko S. Popova L. Tkachenko A. Методичні вказівки для підготовки до практичних занять з біологічної хімії (для студентів медичних факультетів). Частина 2. Біохімія гормонів. Обмін вуглеводів і ліпідів / Упоряд. О.А. Наконечна, С.О. Стеценко, Л.Д. Попова, А.С. Ткаченко. – Харків: ХНМУ, 2016. – 84 с. Упорядники: О.А. Наконечна С.О. Стеценко Л.Д. Попова А.С. Ткаченко - 2 - SOURCES For preparing to practical classes in «Biological Chemistry» Basic Sources 1. Біологічна і біоорганічна хімія: у 2 кн.: підручник. Кн. 2 Біологічна хімія / Ю.І. Губський, І.В. Ніженковська, М.М. Корда, В.І. Жуков та ін.; за ред. Ю.І. Губського, І.В. Ніженковської. – К.: ВСВ «Медицина», 2016. – 544 с. 2. Губський Ю.І. Біологічна хімія. Підручник / Губський Ю.І. – Київ-Вінниця: Нова книга, 2007. – 656 с. 3. Губський Ю.І. Біологічна хімія / Губський Ю.І. – Київ-Тернопіль: Укрмедкнига, 2000. – 508 с. 4. Гонський Я.І. Біохімія людини. Підручник / Гонський Я.І., Максимчук Т.П., Калинський М.І.
    [Show full text]
  • Study of Vesicular Glycolysis in Health and Huntington's Disease
    Study of vesicular glycolysis in health and Huntington’s Disease Maximilian Mc Cluskey To cite this version: Maximilian Mc Cluskey. Study of vesicular glycolysis in health and Huntington’s Disease. Neurons and Cognition [q-bio.NC]. Université Grenoble Alpes [2020-..], 2021. English. NNT : 2021GRALV006. tel-03251320 HAL Id: tel-03251320 https://tel.archives-ouvertes.fr/tel-03251320 Submitted on 7 Jun 2021 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. THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE GRENOBLE ALPES Spécialité : Neurosciences, Neurobiologie Arrêté ministériel : 25 mai 2016 Présentée par Maximilian Mc CLUSKEY Thèse dirigée par Frédéric SAUDOU et co-encadrée par Anne-Sophie NICOT préparée au sein du Grenoble Institut des Neurosciences dans l'École Doctorale de Chimie et Sciences du Vivant Study of vesicular glycolysis in health and Huntington’s disease Thèse soutenue publiquement le 04/02/2021, devant le jury composé de : Mr, Frédéric, DARIOS Chargé de recherche INSERM, Institut du Cerveau, rapporteur Mme, Carine, POURIÉ Professeure
    [Show full text]
  • Pregnant and Early Lactation Dairy Cows: Implications to Liver-Muscle Crosstalk
    RESEARCH ARTICLE Metabolic Response to Heat Stress in Late- Pregnant and Early Lactation Dairy Cows: Implications to Liver-Muscle Crosstalk Franziska Koch1☯, Ole Lamp1,2☯, Mehdi Eslamizad1,3, Joachim Weitzel4, Björn Kuhla1* 1 Institute of Nutritional Physiology “Oskar Kellner”, Leibnitz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany, 2 Schleswig Holstein Chamber of Agriculture, Department of Animal production, Futterkamp, Blekendorf, Germany, 3 Department of Animal Science, Campus of Agriculture and Natural Resources, University of Tehran, Tehran, Iran, 4 Institute of Reproductive Biology, Leibnitz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany a11111 ☯ These authors contributed equally to this work. * [email protected] Abstract OPEN ACCESS Climate changes lead to rising temperatures during summer periods and dramatic eco- nomic losses in dairy production. Modern high-yielding dairy cows experience severe meta- Citation: Koch F, Lamp O, Eslamizad M, Weitzel J, bolic stress during the transition period between late gestation and early lactation to meet Kuhla B (2016) Metabolic Response to Heat Stress in Late-Pregnant and Early Lactation Dairy Cows: the high energy and nutrient requirements of the fetus or the mammary gland, and addi- Implications to Liver-Muscle Crosstalk. PLoS ONE 11 tional thermal stress during this time has adverse implications on metabolism and welfare. (8): e0160912. doi:10.1371/journal.pone.0160912 The mechanisms enabling metabolic adaptation to heat apart from the decline in feed intake Editor: Andrew C. Gill, University of Edinburgh, and milk yield are not fully elucidated yet. To distinguish between feed intake and heat UNITED KINGDOM stress related effects, German Holstein dairy cows were first kept at thermoneutral condi- Received: April 5, 2016 tions at 15°C followed by exposure to heat-stressed (HS) at 28°C or pair-feeding (PF) at Accepted: July 27, 2016 15°C for 6 days; in late-pregnancy and again in early lactation.
    [Show full text]
  • SUPPORT GUIDE Contents ORGANIC ACIDS OXIDATIVE STRESS MARKERS AMINO ACIDS FATTY ACIDS TOXIC and NUTRIENT ELEMENTS
    & SUPPORT GUIDE Contents ORGANIC ACIDS OXIDATIVE STRESS MARKERS AMINO ACIDS FATTY ACIDS TOXIC AND NUTRIENT ELEMENTS Organic Acids NUTRITIONAL Oxidative Stress NUTRITIONAL Amino Acids Plasma NUTRITIONAL Essential & Metabolic Fatty Acids NUTRITIONAL Elements NUTRITIONAL 2. NutrEval Profile The NutrEval profile is the most comprehensive functional and nutritional assessment available. It is designed to help practitioners identify root causes of dysfunction and treat clinical imbalances that are inhibiting optimal health. This advanced diagnostic tool provides a systems-based approach for clinicians to help their patients overcome chronic conditions and live a healthier life. The NutrEval assesses a broad array of macronutrients and micronutrients, as well as markers that give insight into digestive function, toxic exposure, mitochondrial function, and oxidative stress. It accomplishes this by evaluating organic acids, amino acids, fatty acids, oxidative stress markers, and nutrient & toxic elements. Subpanels of the NutrEval are also available as stand-alone options for a more focused assessment. The NutrEval offers a user-friendly report with clinically actionable results including: • Nutrient recommendations for key vitamins, minerals, amino acids, fatty acids, and digestive support based on a functional evaluation of important biomarkers • Functional pillars with a built-in scoring system to guide therapy around needs for methylation support, toxic exposures, mitochondrial dysfunction, fatty acid imbalances, and oxidative stress • Interpretation-At-A-Glance pages providing educational information on nutrient function, causes and complications of deficiencies, and dietary sources • Dynamic biochemical pathway charts to provide a clear understanding of how specific biomarkers play a role in biochemistry There are various methods of assessing nutrient status, including intracellular, extracellular, direct, and functional measurements.
    [Show full text]
  • GLUCONEOGENESIS Defined As Biosynthesis of Glucose from Non
    GLUCONEOGENESIS Defined as biosynthesis of glucose from non-carbohydrate precursors. Gluconeogenesis is the biosynthesis of new glucose from non-carbohydrate substances such as pyruvate lactate Glycosylated amino acids Propionic acid derived from odd chain fatty acids Glycerol part of fat. It takes place mainly in liver and to a lesser extent in renal cortex. The cycle is partly in mitochondrial and partly in cytoplasmic Sources for Gluconeogenesis Alanine: It is produced from other amino acids derived from tissue protein break down Glycerol: lipid mobilization from adipose tissue & lipolysis Lactate: anaerobic glycolysis in tissues such as working muscle or RBCs Propionate: from odd chain length fatty acids The one which is helping when body really needs glucose is Glucogenic Aminoacids especially Alanine Cori’s cycle The cycle involving synthesis of glucose in liver from the skeletal muscle lactate and the reuse of glucose by the muscle for energy purpose is known as cori cycle Transferring lactate from tissue to liver and synthesis of glucose is known as cori’s cycle. Effects It rescues lactate for further use (gluconeogenesis) It counteracts lactic acidosis. It is of less importance in starvation but important in more normal situations especially in certain cells such as matured RBC, medulla, retina which are lacking mitochondria and virtually anaerobic. It does not consume any energy Pyruvate to Phosphoenolpyruvate Endergonic & requires free energy input. This is accomplished by first converting the pyruvate to oxaloacetate, a “high-energy” intermediate. CO2 is added to pyruvate by pyruvate carboxylase enzyme. CO2 that was added to pyruvate to form OAA is released in the reaction catalyzed by phosphoenolpyruvate carboxykinase (PEPCK) to form PEP, Exergonic decarboxylation OAA provides the free energy necessary for PEP synthesis.
    [Show full text]
  • Inhibition of the Oxygen Sensor PHD2 in the Liver Improves Survival in Lactic Acidosis by Activating the Cori Cycle
    Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle Tomohiro Suharaa,b,1, Takako Hishikia,c,d,e,1, Masataka Kasaharaa,f,1, Noriyo Hayakawaa,c,d, Tomoko Oyaizua,b, Tsuyoshi Nakanishia,g, Akiko Kuboa,d, Hiroshi Morisakib, William G. Kaelin Jr.h,i,2, Makoto Suematsua,d,2, and Yoji Andrew Minamishimaa,d,2 aDepartment of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; bDepartment of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan; cTranslational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan; dJapan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; eJapan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; fDepartment of Pharmacology, Tokyo Dental College, Tokyo 101-0061, Japan; gMS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan; hDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215; and iHoward Hughes Medical Institute, Chevy Chase, MD 20815 Contributed by William G. Kaelin, Jr., August 12, 2015 (sent for review June 22, 2015; reviewed by Ralph J. DeBerardinis) Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible Results and Discussion factor-dependent hypoxic response, including anaerobic glycolysis, Inactivation of Phd2 in the Liver Reduces the Blood Lactate Level. which causes large amounts of lactate to be released from cells into PHD2 is the dominant HIF-prolyl hydroxylase in vivo among all the circulation.
    [Show full text]
  • Physiological and Metabolic Adaptations to Different Photoperiods: Effects of Obesity and Seasonal Fruit Consumption
    PHYSIOLOGICAL AND METABOLIC ADAPTATIONS TO DIFFERENT PHOTOPERIODS: EFFECTS OF OBESITY AND SEASONAL FRUIT CONSUMPTION Roger Mariné Casadó ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral.
    [Show full text]
  • Metabolite Profiling of LADA Challenges the View of a Metabolically Distinct Subtype
    Page 1 of 33 Diabetes Metabolite profiling of LADA challenges the view of a metabolically distinct subtype Mahmoud Al-Majdoub1,*, Arslan Ali1,2*, Petter Storm3, Anders Rosengren4, Leif Groop1,5, and Peter Spégel1,6 1 Unit of Molecular Metabolism, Department of Clinical Sciences in Malmö, Lund University, SE-20502 Malmö, Sweden. 2 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan 3 Diabetes and Endocrinology, Department of Clinical Sciences in Malmö, Lund University, SE-20502 Malmö, Sweden. 4 Translational Diabetes Research, Department of Clinical Sciences in Malmö, Lund University, SE-20502 Malmö, Sweden. 5 Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland. 6 Centre for Analysis and Synthesis, Department of Chemistry, Lund University, SE- 221 00 Lund, Sweden. * Equal contribution Keywords: Metabolism; latent autoimmune diabetes in adults; type 1 diabetes; type 2 diabetes; metabolomics. Word count: 2868 Number of Figures: 3 Number of tables: 3 Running title: The metabolite profile of diabetes Corresponding author: Peter Spégel, Department of Chemistry, Centre for Analysis and Synthesis, Naturvetarvägen 14, 223 62 Lund, Sweden. Email: [email protected], Tel: +46-40-391009 1 Diabetes Publish Ahead of Print, published online December 2, 2016 Diabetes Page 2 of 33 ABSTRACT Latent autoimmune diabetes in adults (LADA) usually refers to GADAb positive diabetes with onset after 35 years of age and no insulin treatment within the first 6 months after diagnosis. However, it is not always easy to distinguish LADA from type 1 or type 2 diabetes. In this study we examined whether metabolite profiling could help to distinguish LADA (N=50) from type 1 (N=50) and type 2 diabetes (N=50).
    [Show full text]