DOCSLIB.ORG

Cc By-Nc-Nd 2.0)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cc By-Nc-Nd 2.0) http://portaildoc.univ-lyon1.fr Creative commons : Paternité - Pas d’Utilisation Commerciale - Pas de Modification 2.0 France (CC BY-NC-ND 2.0) http://creativecommons.org/licenses/by-nc-nd/2.0/fr FOURNIE (CC BY-NC-ND 2.0) UNIVERSITÉ CLAUDE BERNARD - LYON 1 FACULTÉ DE MÉDECINE LYON EST Année 2017 - N° 139 IMPACT DE LA TRANSPLANTATION PANCRÉATICO DUODÉNALE SUR LE MÉTABOLISME DES ACIDES BILIAIRES ET DES INCRÉTINES ÉTUDE ITABI THÈSE Présentée à l'université Claude Bernard - Lyon 1 Et soutenue publiquement le 15 septembre 2017 Pour obtenir le grade de Docteur en Médecine Par Coralie FOURNIE Née le 9 juin 1988 à Lyon FOURNIE (CC BY-NC-ND 2.0) FOURNIE (CC BY-NC-ND 2.0) UNIVERSITÉ CLAUDE BERNARD - LYON 1 FACULTÉ DE MÉDECINE LYON EST Année 2017 - N° 139 IMPACT DE LA TRANSPLANTATION PANCRÉATICO DUODÉNALE SUR LE MÉTABOLISME DES ACIDES BILIAIRES ET DES INCRÉTINES ÉTUDE ITABI THÈSE Présentée à l'université Claude Bernard - Lyon 1 Et soutenue publiquement le 15 septembre 2017 Pour obtenir le grade de Docteur en Médecine Par Coralie FOURNIE Née le 9 juin 1988 à Lyon FOURNIE (CC BY-NC-ND 2.0) 1 FOURNIE (CC BY-NC-ND 2.0) 2 FOURNIE (CC BY-NC-ND 2.0) 3 FOURNIE (CC BY-NC-ND 2.0) 4 FOURNIE (CC BY-NC-ND 2.0) 5 FOURNIE (CC BY-NC-ND 2.0) 6 FOURNIE (CC BY-NC-ND 2.0) REMERCIEMENTS À NOTRE PRÉSIDENT DE THÈSE : Monsieur le Professeur E. MORELON, Pour avoir accepté la présidence de ce travail. Nous avons eu la chance de croiser tôt son chemin et celui de la néphrologie et le remercions très sincèrement pour l’écoute permanente qu’il a su nous accorder au cours de ces huit dernières années. Nous avons eu le privilège de bénéficier à plusieurs reprises de la qualité de son enseignement, et nous continuerons à nous inspirer de sa présence et de ses grandes compétences cliniques pour devenir meilleure néphrologue. Qu’il soit assuré de notre profond respect. 7 FOURNIE (CC BY-NC-ND 2.0) À NOS JUGES : Monsieur le Professeur L. BADET, Pour nous avoir fait l’honneur de s’intéresser à ce travail. Nous savons l’intérêt qu’il porte à l’échange quotidien entre exercice médical et chirurgical en transplantation et espérons avoir respecté les mêmes principes que lui et son équipe. Qu’il trouve ici le témoignage de notre reconnaissance. Monsieur le Professeur O. THAUNAT, Pour avoir accepté de juger ce travail. Nous avons été honorée d’avoir pu apprendre et pratiquer sous ses conseils avisés au cours de notre internat. Nous avons apprécié sa rigueur et son haut niveau d’exigence. Nous sollicitons son indulgence et l’assurons de notre grande estime. Madame le Professeur F. GUEBRE-EGZIABHER (Directrice de thèse), Pour son exceptionnel encadrement de notre travail de mémoire puis de thèse. Son art de l’enseignement et sa bienveillance nous ont permis d’apprendre la rigueur scientifique de la recherche clinique et de la rédaction d’articles. Son désir de transmission, de partage, nous a fait progresser en confiance. Qu’elle soit assurée de notre gratitude et surtout de notre profonde admiration. Madame le Docteur S. LEMOINE (Maître de Conférence des Universités), Pour avoir accepté de juger ce travail et avoir participé au recrutement de nos patients. Nous avons pu bénéficier lors de notre passage au pavillon P de son implication dans la formation des internes et de ses qualités organisationnelles, dans la bonne humeur permanente. 8 FOURNIE (CC BY-NC-ND 2.0) À MA FAMILLE : À mon mari, pour notre voyage. À ma mère, pour son amour et son soutien précieux. À mon père, pour sa tendresse. J’essaierai d’être un aussi bon docteur Fournie que lui. À ma sœur, pour rester proche malgré la distance et toujours me faire rire. Au premier docteur Guy Fournie et à ma grand-mère Jacqueline Fournie, qui m’inspire par sa volonté et sa force. Nos échanges restent des moments privilégiés. À mes grands-parents Jacques et André Arlin, pour leurs sourires, leur amour de la nature et de la table. Mon Papili tu me manques tant. À ma tante Bénédicte, à ma petite cousine Agathe (mio pulcino), la branche italienne de la famille. À ma tante et mon oncle, Sylvère et Hervé À mes cousins Sarène, Lyonel, Gaël, Vianney À ma marraine Sophie À mon parrain Régis et ma parraine Martine À ma belle-famille À mon petit chien Giotto 9 FOURNIE (CC BY-NC-ND 2.0) À MES COLLÈGUES : À toute l’équipe de transplantation de P2, A tous les médecins, pour m’avoir encadrée et accompagnée, et plus particulièrement à Fanny et à Cécile pour leur bonté et leurs rires, et au docteur Cahen pour son temps et son expérience. A toutes les infirmières (et l’infirmier) et à l’équipe aide-soignante pour leur accueil et leur amitié. À toute l’équipe médicale et paramédicale de néphrologie de P1, Notamment à monsieur le professeur Juillard pour sa bienveillance, au Dr Jolivot pour sa bonne humeur et ses conseils et au Dr Sens pour son aide précieuse en biostatistiques. À mes amis néphrologues du Tonkin, Aux docteurs Solenne Linca, Marine Panaye, Alexandre Karamé, François Combarnous, Jérôme Finaz-de-Villaine, pour leur bonté, leur gentillesse, leur pédagogie, les biopsies et leur confiance. À mes amis néphrologues du Centre du Rein Artificiel de Tassin-Charcot, Christie Lorriaux, Manolie Mehdi, Jean-Marc Hurot, Brice Mayor, Guillaume Jean, Patrik Deleaval, Charles Chazot, pour leur riche formation sur l’épuration extrarénale, les cathéters, les congrès, les posters, leur accueil, leur humanité et leur confiance. À l’équipe de néphrologie de Lyon-Sud, Notamment à ma première assistante Amélie pour le début de ma formation, au docteur Trolliet pour la transmission de son savoir, au docteur Pelletier pour l’encadrement de mon mémoire. À mes co-internes, À Flora, Gabrielle, Anne, pour partager le meilleur et supporter le pire. A Pascaline, Eric et Thomas, même si vous avez été mes assistants, Nans, Cécile, Lucien, Marion, François, Arthur, Jean-Pierre, pour m’avoir fait rire et accompagnée. A mes « petits » préférés Maxime X3, Elodie, Xiao fan. 10 FOURNIE (CC BY-NC-ND 2.0) À ma famille carabine : Aline, Antoine F, Antoine V, Aurélie, Axelle, Bruno, Caroline, Fanny, Kristina, Laura, Louis, Marion, Pierre, Razvan, Sophie, Vincent ; À ma proche belle-famille carabine : Alice, Allyriane, Benjamin, Blandine, Gautier, Killien, Marine, Mélissa, et aux enfants de la communauté : Juliette, Eliott, Malo, Arsène… Pour les 12 ans de survie commune et de partages. À mes amis de et pour toujours : Camille E, Marie D et Marie-Laure, Clément, Maud, Camille et François (et Salomé), Marie F, Adélaïde, Pauline, Virginie, Aude. Pour leur présence et leurs encouragements. À Anna san et Akio sensei Ces remerciements s’étendent à toutes les personnes qui me font l’amitié d’assister à la soutenance de cette thèse. 11 FOURNIE (CC BY-NC-ND 2.0) TABLE DES ABRÉVIATIONS AB Acides biliaires AC Acide cholique ACDC Acide chénodéoxycholique ADC Acide déoxycholique ALC Acide lithocholique ASBT Apical Sodium Bile Acid Transporter AUC Area Under the Curve AUDC Acide ursodéoxycholique BMI Body Mass Index BSEP Bile Salt Export Pump CKD-EPI Chronic Kidney Disease - Epidemiology Collaboration CRNH Centre de Recherche en Nutrition Humaine CRP C Reactive Protein CYP27A1 Stérol 27-hydroxylase CYP7A1 Cholesterol 7α-hydroxylase CYP7B1 Oxysterol 7α-hydroxylase CYP8B1 Stérol 12α-hydroxylase DPP4 Dipeptidyl Peptidase 4 DT2 Diabète de Type 2 FGF 19 Fibroblast Growth Factor 19 FGFR4 FGF Receptor 4 FXR Farnesoid X Receptor GLP-1 Glucagon Like Peptide-1 GLUT Glucose Transporter HbA1c Hémoglobine glyquée HGPO HyperGlycémie Provoquée par voie Orale HOMA-IR Homeostasis Model Assessment of Insulin Resistance HSD 3β 3 -Hydroxy-D5-C27-steroid dehydroxylase IGI Indice Insulinogénique IMC Indiceβ de Masse Corporelle IPTR International Pancreas Transplant Registry IRS Insulin Receptor Substrate KT Kidney Transplantation MAPK-ERK Mitogen-activated protein kinase/Extracellular signal-regulated kinase MMF Mycophenolate mofetyl NTCP Na+ dependent taurocholate transporter OGTT Oral Glucose Tolerance Test PKB Protein kinase B PI3K Phosphatidyl Inositol 3 Kinase PIP3 Phosphatidyl Inositol 3 Phosphate QUICKI Quantitative Insulin Sensitivity Check Index SHP Small heterodimer partner SPKT Simultaneous Pancreas Kidney Transplantation T1D Type 1 Diabetes T2DM Type 2 Diabetes Mellitus TGR5 Takeda-G-protein-receptor-5 12 FOURNIE (CC BY-NC-ND 2.0) TABLE DES MATIÈRES INTRODUCTION 14 REVUE DE LA LITTÉRATURE 16 I. TRANSPLANTATION PANCRÉATIQUE 16 I. 1. INDICATION 16 I. 2. MODALITÉS CHIRURGICALES 16 I. 3. SUIVI 18 II. RÉGULATION DE L'HOMÉOSTASIE DU GLUCOSE 20 II. 1. INSULINE 20 II. 1. 1. INSULINOSECRETION 20 II. 1. 2. INSULINO-RESISTANCE 21 II. 1. 3. INSULINORESISTANCE ET TRANSPLANTATION PANCREATIQUE 22 II. 2. GLUCAGON 25 III. ACIDES BILIAIRES : ROLE SIGNALÉTIQUE 26 III. 1. MÉTABOLISME 26 III. 1. 1. SYNTHESE 26 III. 1. 2. CYCLE ENTERO-HEPATIQUE 28 III. 2. ROLE SIGNALÉTIQUE ET INTERACTION AVEC LE MICROBIOTE INTESTINAL 31 IV. RÉGULATEURS DU GLUCOSE ET ACIDES BILIAIRES 34 IV. 1. VOIE DE RÉGULATION TGR5/GLP-1 34 IV. 1. 1. TGR5 34 IV. 1. 2. GLP-1 : EFFET INCRETINE 35 IV. 2. VOIE DE RÉGULATION FXR/FGF 19 37 IV. 2. 1. FXR 37 IV. 2. 2. FGF 19 39 IMPACT OF PANCREAS TRANSPLANTATION ON BILE ACIDS AND GLUCOSE METABOLISM41 TABLES ET FIGURES 57 CONCLUSIONS 66 RÉFÈRENCES 69 13 FOURNIE (CC BY-NC-ND 2.0) INTRODUCTION La transplantation rénale est la transplantation d’organe vascularisé la plus fréquente en France. Non vitale, elle représente cependant le traitement à privilégier pour les patients présentant une insuffisance rénale chronique terminale. Parmi ces patients, ceux atteints d’un diabète de type I peuvent bénéficier d’une transplantation combinée rein- pancréas.
Load more

Recommended publications
  • Review: Microbial Transformations of Human Bile Acids Douglas V
    Guzior and Quinn Microbiome (2021) 9:140 https://doi.org/10.1186/s40168-021-01101-1 REVIEW Open Access Review: microbial transformations of human bile acids Douglas V. Guzior1,2 and Robert A. Quinn2* Abstract Bile acids play key roles in gut metabolism, cell signaling, and microbiome composition. While the liver is responsible for the production of primary bile acids, microbes in the gut modify these compounds into myriad forms that greatly increase their diversity and biological function. Since the early 1960s, microbes have been known to transform human bile acids in four distinct ways: deconjugation of the amino acids glycine or taurine, and dehydroxylation, dehydrogenation, and epimerization of the cholesterol core. Alterations in the chemistry of these secondary bile acids have been linked to several diseases, such as cirrhosis, inflammatory bowel disease, and cancer. In addition to the previously known transformations, a recent study has shown that members of our gut microbiota are also able to conjugate amino acids to bile acids, representing a new set of “microbially conjugated bile acids.” This new finding greatly influences the diversity of bile acids in the mammalian gut, but the effects on host physiology and microbial dynamics are mostly unknown. This review focuses on recent discoveries investigating microbial mechanisms of human bile acids and explores the chemical diversity that may exist in bile acid structures in light of the new discovery of microbial conjugations. Keywords: Bile acid, Cholic acid, Conjugation, Microbiome, Metabolism, Microbiology, Gut health, Clostridium scindens, Enterocloster bolteae Introduction the development of healthy or diseased states. For The history of bile example, abnormally high levels of the microbially modi- Bile has been implicated in human health for millennia.
    [Show full text]
  • Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease
    nutrients Review Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease Cong Xie 1,† , Weikun Huang 1,2,† , Richard L. Young 1,3 , Karen L. Jones 1,4 , Michael Horowitz 1,4, Christopher K. Rayner 1,5 and Tongzhi Wu 1,4,6,* 1 Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; [email protected] (C.X.); [email protected] (W.H.); [email protected] (R.L.Y.); [email protected] (K.L.J.); [email protected] (M.H.); [email protected] (C.K.R.) 2 The ARC Center of Excellence for Nanoscale BioPhotonics, Institute for Photonics and Advanced Sensing, School of Physical Sciences, The University of Adelaide, Adelaide 5005, Australia 3 Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute, Adelaide 5005, Australia 4 Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia 5 Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5005, Australia 6 Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and Citation: Xie, C.; Huang, W.; Young, the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge R.L.; Jones, K.L.; Horowitz, M.; regarding bile acid physiology and metabolic health.
    [Show full text]
  • Resistant Starch Can Improve Insulin Sensitivity Independently of the Gut Microbiota Laure B
    Bindels et al. Microbiome (2017) 5:12 DOI 10.1186/s40168-017-0230-5 RESEARCH Open Access Resistant starch can improve insulin sensitivity independently of the gut microbiota Laure B. Bindels1, Rafael R. Segura Munoz1, João Carlos Gomes-Neto1, Valentin Mutemberezi2, Inés Martínez3, Nuria Salazar4, Elizabeth A. Cody1, Maria I. Quintero-Villegas1, Hatem Kittana1, Clara G de los Reyes-Gavilán4, Robert J. Schmaltz1, Giulio G. Muccioli2, Jens Walter3,5 and Amanda E. Ramer-Tait1* Abstract Background: Obesity-related diseases, including type 2 diabetes and cardiovascular disease, have reached epidemic proportions in industrialized nations, and dietary interventions for their prevention are therefore important. Resistant starches (RS) improve insulin sensitivity in clinical trials, but the mechanisms underlying this health benefit remain poorly understood. Because RS fermentation by the gut microbiota results in the formation of physiologically active metabolites, we chose to specifically determine the role of the gut microbiota in mediating the metabolic benefits of RS. To achieve this goal, we determined the effects of RS when added to a Western diet on host metabolism in mice with and without a microbiota. Results: RS feeding of conventionalized mice improved insulin sensitivity and redressed some of the Western diet-induced changes in microbiome composition. However, parallel experiments in germ-free littermates revealed that RS-mediated improvements in insulin levels also occurred in the absence of a microbiota. RS reduced gene expression of adipose tissue macrophage markers and altered cecal concentrations of several bile acids in both germ-free and conventionalized mice; these effects were strongly correlated with the metabolic benefits, providing a potential microbiota-independent mechanism to explain the physiological effects of RS.
    [Show full text]
  • Mechanisms of Drug-Induced Liver Injury: the Role of Hepatic Transport Proteins
    MECHANISMS OF DRUG-INDUCED LIVER INJURY: THE ROLE OF HEPATIC TRANSPORT PROTEINS Kyunghee Yang A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy Chapel Hill 2014 Approved by: Kim L.R. Brouwer Paul B. Watkins Dhiren Thakker Harvey J. Clewell III Brett A. Howell ©2014 Kyunghee Yang ALL RIGHTS RESERVED ii ABSTRACT Kyunghee Yang: Mechanisms of Drug-Induced Liver Injury: The Role of Hepatic Transport Proteins (Under the direction of Kim L.R. Brouwer) The objectives of this research were to investigate mechanisms of drug-induced liver injury (DILI) that involve drug-bile acid (BA) interactions at hepatic transporters, and develop a novel strategy to reliably predict human DILI. Troglitazone (TGZ), an antidiabetic withdrawn from the market due to severe DILI, was employed as a model hepatotoxic drug. Pharmacokinetic modeling of taurocholic acid (TCA, a model BA) disposition data from human and rat sandwich-cultured hepatocytes (SCH) revealed that species differences exist in TCA hepatocellular efflux pathways; in human SCH, TCA biliary excretion predominated, whereas biliary and basolateral excretion contributed equally to TCA efflux in rat SCH. This finding explains, in part, why rats are less susceptible to DILI compared to humans after administration of drugs that inhibit BA biliary excretion. The present study also revealed for the first time that TGZ sulfate (TS), a major TGZ metabolite, inhibits BA basolateral efflux in addition to biliary excretion. These findings support the hypothesis that TS is an important mediator of altered hepatic BA disposition; increased hepatic TS exposure due to impaired canalicular transport function might predispose a subset of patients to hepatotoxicity.
    [Show full text]
  • University of California Riverside
    UNIVERSITY OF CALIFORNIA RIVERSIDE Modulation of Vibrio cholerae Virulence Pathway through Microbiome Metabolism of Bile Acids . A Thesis submitted in partial satisfaction of the requirements for the degree of Master of Science in Microbiology by Jonathan David Mitchell September 2019 Thesis Committee: Dr. Ansel Hsiao, Chair Dr. Patrick Degnan Dr. Rong Hai Copyright by Jonathan David Mitchell 2019 The Thesis of Jonathan David Mitchell is approved: Committee Chairperson University of California, Riverside Dedication To my parents for fostering my love in science and being there for me even in the rough times. To my fiancée Elizabeth Deyett for encouraging me to further my education, supporting me though this endeavor and being my rock. iv Acknowledgements I would like to acknowledge Salmasadat Alavi, the graduate student in Dr. Ansel Hsiao’s lab for developing the infant mouse model used in my research. I would like to acknowledge Jennifer Cho the graduate student in Dr. Ansel Hsiao’s Lab for developing the Escherichia coli strains that expresses Blautia obeum Bile Salt Hydrolase and Blautia obeum Autoinducer-2 molecules. I would also like to acknowledge John Macbeth, and Rui Liu, the graduate students in Dr. Ansel Hsiao’s Lab for helping me in my own work. Finally, I would like to thank Jay Kirkwood. With his help, we were able to identify bile acid species in our samples leading to the identification of bile salt hydrolase. v Table of Contents Dedication………………………………………………………………………………...iv Acknowledgements………………………………………………………………………..v
    [Show full text]
  • Species Differences of Bile Acid Redox Metabolism: Tertiary Oxidation of Deoxycholate Is Conserved in Preclinical Animals
    DMD Fast Forward. Published on March 19, 2020 as DOI: 10.1124/dmd.120.090464 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 090464 Title page Species Differences of Bile Acid Redox Metabolism: Tertiary Oxidation of Deoxycholate is Conserved in Preclinical Animals Qiuhong Lin1,4,*, Xianwen Tan1,4,*, Wenxia Wang1,4, Wushuang Zeng1,4, Lanlan Gui1,4, Mingming Su2, Changxiao Liu3, Wei Jia2, Liang Xu1, Ke Lan1,4,# 1 Key laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West Downloaded from China School of Pharmacy, Sichuan University, Chengdu, China. 2 Metabolomics Shared Resource, University of Hawaii Cancer Center, Honolulu, HI, United States. dmd.aspetjournals.org 3 State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China. 4 Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China. at ASPET Journals on September 29, 2021 Page 1 of 27 DMD Fast Forward. Published on March 19, 2020 as DOI: 10.1124/dmd.120.090464 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 090464 Running Title Page Species Differences of Bile Acid Redox Metabolism # Corresponding authors Ke Lan, PhD West China School of Pharmacy, Sichuan University No.17 People's South Road, Chengdu, 610041 China Tel: +86 02885503722 Downloaded from E-mail: [email protected] Number of text pages: 29 Number of tables: 0 dmd.aspetjournals.org Number of figures: 6 Number of references: 56 Words in Abstract: 240 at ASPET Journals on September 29, 2021 Words in Introduction: 1081 Words in Methods: 1129 Words in Results: 1269 Words in Discussion: 1155 Page 2 of 27 DMD Fast Forward.
    [Show full text]
  • Sulphated and Unsulphated Bile Acids in Serum, Bile, and Urine of Patients with Cholestasis1
    Gut: first published as 10.1136/gut.17.11.861 on 1 November 1976. Downloaded from Gut, 1976, 17, 861-869 Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis1 G. P. VAN BERGE HENEGOUWEN2, K-H. BRANDT, H. EYSSEN, AND G. PARMENTIER From the Department of Internal Medicine, Municipal Hospital, Arnhem, The Netherlands; Rega Institute, Louvain, Belgium SUMMARY Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (> 93 %) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (> 60 %) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount ofbile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71 6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxy- cholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in http://gut.bmj.com/ the differential diagnosis of cholestasis.
    [Show full text]
  • Glucuronidation of 6A-Hydroxy Bile Acids by Human Liver Microsomes Anna Radominska-Pyrek,* Piotr Zimniak,* Yacoub M
    Glucuronidation of 6a-Hydroxy Bile Acids by Human Liver Microsomes Anna Radominska-Pyrek,* Piotr Zimniak,* Yacoub M. Irshaid,t Roger Lester,* Thomas R. Tephly,t and Jan St. Pyrek *Division of Gastroenterology, Department ofInternal Medicine, University of Texas Medical School at Houston, Houston, Texas 77225; *Department ofPharmacology, University ofIowa, Iowa City, Iowa 52242; §Department ofBiochemistry, Jzice University, Houston, Texas 77251 Abstract accumulation of cytotoxic mono- and dihydroxylated bile acids in this disease; details of this viewpoint will be discussed later. The glucuronidation of 6-hydroxylated bile acids by human liver A certain amount of disagreement exists in the literature nicrosomes has been studied in vitro; for comparison, several concerning the presence of bile acid 6a-hydroxylase activity in ,major bile acids lacking a 6-hydroxyl group were also investi- human tissues. Whereas Bjorkhem et al. (12) could not detect gated. Glucuronidation rates for 6a-hydroxylated bile acids were any appreciable hydroxylation of lithocholate, taurolithocholate, 10-20 times higher than those of substrates lacking a hydroxyl and taurochenodeoxycholate by isolated human liver micro- group in position 6. The highest rates measured were for hyode- somes in the presence of NADPH, Trulzsch et al. (6) found qxy- and hyocholic acids, and kinetic analyses were carried out conversion of taurolithocholate to taurohyodeoxycholate under using these substrates. Rigorous product identification by high- similar conditions. The lack of a 6a-hydroxylase would be, how- field proton nuclear magnetic resonance and by electron impact ever, inconsistent with the well-documented occurrence of 6a- mass spectrometry of methyl ester/peracetate derivatives re- hydroxylated bile acids in humans: no bacterial hydroxylation vealed that 6-O-jD-glucuronides were the exclusive products of bile acids is known to take place in the gut (13, 14), and formed in these enzymatic reactions.
    [Show full text]
  • Factors Affecting Separation and Detection of Bile Acids by Liquid Chromatography Coupled with Mass Spectrometry in Negative Mode
    Anal Bioanal Chem DOI 10.1007/s00216-017-0489-1 RESEARCH PAPER Factors affecting separation and detection of bile acids by liquid chromatography coupled with mass spectrometry in negative mode Shanshan Yin1 & Mingming Su2,3 & Guoxiang Xie3 & Xuejing Li4 & Runmin Wei3 & Changxiao Liu5 & Ke Lan1,3 & Wei Jia 3 Received: 10 April 2017 /Revised: 13 June 2017 /Accepted: 22 June 2017 # Springer-Verlag GmbH Germany 2017 Abstract Bile acids (BAs) are cholesterol metabolites with hydroxylation. It was also found that the retention of taurine important biological functions. They undergo extensive host- conjugates on the BEH C18 column was sensitive to the gut microbial co-metabolisms during the enterohepatic circu- strength of formic acid and ammonium in mobile phases. By lation, creating a vast structural diversity and resulting in great using the volatile buffers with an equivalent ammonium level challenges to separate and detect them. Based on the as mobile phases, we comprehensively demonstrated the ef- bioanalytical reports in the past decade, this work developed fects of the elution pH value on the retention behaviors of BAs three chromatographic gradient methods to separate a total of on both the BEH C18 column and HSS T3 column. Based on 48 BA standards on an ethylene-bridged hybrid (BEH) C18 the retention data acquired on a C18 column, we presented the column and high-strength silica (HSS) T3 column and accord- ionization constants (pKa) of various BAs with the widest ingly unraveled the factors affecting the separation and detec- coverage beyond those of previous reports. When we made tion of them by liquid chromatography coupled with mass attempts to establish the structure-retention relationships spectrometry (LC-MS).
    [Show full text]
  • Pbdes Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice
    DMD Fast Forward. Published on May 16, 2018 as DOI: 10.1124/dmd.118.081547 This article has not been copyedited and formatted. The final version may differ from this version. DMD # #81547 PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice Cindy Yanfei Li, Joseph L. Dempsey, Dongfang Wang, Soowan Lee, Kris M. Weigel, Qiang Fei, Deepak Kumar Bhatt, Bhagwat Prasad, Daniel Raftery, Haiwei Gu, and Julia Yue Cui Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA (CYF, JLD, KMW, SL, and JYC); Northwest Metabolomics Research Downloaded from Center, Department of Anesthesiology and Pain Medicine, University of Washington, 850 Republican St., Seattle, WA 98109, USA (DW, QF, and DR); Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of dmd.aspetjournals.org Health Solutions, Arizona State University, Phoenix, AZ 85004, USA (HG); Department of Pharmaceutics, University of Washington, Seattle, WA 98105, USA (DKB, BP); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing at ASPET Journals on September 24, 2021 100191, P. R. China (DF); Department of Chemistry, Jilin University, Changchun, Jilin Province 130061, P. R. China (QF). 1 DMD Fast Forward. Published on May 16, 2018 as DOI: 10.1124/dmd.118.081547 This article has not been copyedited and formatted. The final version may differ from this version. DMD # #81547 Running title: Effect of PBDEs
    [Show full text]
  • Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats
    J Nutr Sci Vitaminol, 65, 45–51, 2019 Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats Reika YOSHITSUGU, Keidai KIKUCHI, Hitoshi IWAYA, Nobuyuki FUJII, Shota HORI, Dong Geun LEE and Satoshi ISHIZUKA* Laboratory of Nutritional Biochemistry, Research Group of Bioscience and Chemistry, Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo 060–8589, Japan (Received July 3, 2018) Summary Ingestion of a high-fat (HF) diet is known to enhance bile acid (BA) secretion, but precise information about the BA molecular species is lacking, especially information on the conjugated BAs in enterohepatic circulation. As cholesterol is the precursor of BAs, we analyzed alterations of the entire BA metabolic pathway in response to a HF diet without the addition of cholesterol and BA in the diet. Additionally, we evaluated the relationships between BA metabolism and some disorders, such as plasma transaminase activities and glucose intolerance induced by the HF diet. Acclimated WKAH/HkmSlc male rats (3 wk old) were divided into two groups fed a control or the HF diet for 22 wk. Fasting blood glu- cose was measured during the experimental period, and an intraperitoneal glucose tolerance test was performed at week 21. As a result, ingestion of the HF diet selectively increased the concentration of taurocholic acid in the bile and small intestinal contents as well as deoxycholic acid in the large intestinal contents and feces. These results indicated a selec- tive increase of 12a-hydroxylated BA concentrations in response to the HF diet.
    [Show full text]
  • Table S1. List of Liver, Fecal, Serum Bile Acid, and Internal Standards (IS) Names and Abbreviations
    Table S1. List of liver, fecal, serum bile acid, and internal standards (IS) names and abbreviations. Abbreviation Bile Acid Name 12 KLCA 3α-Hydroxy-12 Ketolithocholic Acid 3, 7, 12 DHCA 3,7,12 Dehydrocholic acid 3,12-DKCA 3,12-Diketocholanic Acid 3,6-DKCA 3,6-Diketocholanic Acid 3,7-DKCA 3,7-Diketocholanic Acid 3-EpiDCA 5β-Cholanic Acid-3β, 12α-diol 5β-CA-3a,6a-diol-7-one 5β-Cholanic Acid-3α, 6α-diol-7-one 5β-CA-7a-ol-3-one 5β-Cholenic Acid-7α-ol-3-one 8(14), 5β-CA-3α, 12α-diol 8(14), 5β-Cholenic Acid-3α, 12α-diol 7 KLCA 3α-Hydroxy-7 Ketolithocholic Acid 7, 12 DKCA 3α-Hydroxy-7,12-Diketocholanic Acid 9(11)-CA 9(11), (5β)-Cholenic Acid-3α-ol-12-one ALCA Allolithocholic Acid AlloCA Allocholanic acid ApoCA Apocholic acid CA Cholic acid CDCA Chenodeoxycholic acid DCA Deoxycholic acid DHCA 3-Dehydrocholic Acid GDCA Glycodeoxycholic acid GLCA Glycolithocholic Acid HCA Hyocholic acid HDCA Hyodeoxycholic acid IsoDCA Isodeoxycholic Acid IsoLCA Isolithocholic Acid KCA 3-Ketocholanic Acid LC Lithocholic acid LCA Lithocholenic acid MuriDCA Murideoxycholic acid MuroCA Murocholic Acid norDCA 3α,12α, 23-Nordeoxycholic Acid TCA Taurocholic acid TCDCA Taurochenodeoxycholic acid TDCA Taurodeoxycholic acid THCA Taurohyocholic Acid THDCA Taurohyodeoxycholic Acid TLCA Taurolithocholic Acid TUCA Tauro-ursocholanic Acid TUDCA Tauroursodeoxycholic acid TαMCA Tauro-β-muricholic acid TβMCA Tauro-α-muricholic acid TωMCA Tauro-ω-muricholic acid UCA Ursocholanic Acid UDCA Ursodeoxycholic acid αMCA Alpha-Muricholic acid βMCA Beta- Muricholic acid ωMCA Omega- Muricholic acid LC-d4 (IS) Lithocholic Acid-d4 DCA-d4 (IS) Deoxycholic Acid-d4 CDCA-d4 (IS) Chenodeoxycholic Acid-d4 UDCA-d4 (IS) Ursodeoxycholic Acid-d4 HDCA-d4 (IS) Hyodeoxycholic Acid-d5 CA-d4 (IS) Cholic Acid-d4 GLCA-d4 (IS) Glycolithocholic Acid-d4 GCDCA-d4 (IS) Glycochenodeoxycholic Acid-d4 GDCA-d4 (IS) Glycodeoxycholic Acid-d4 GUDCA-d4 (IS) Glycoursodeoxycholic Acid-d4 GCA-d4 (IS) Glycocholic Acid-d4 TLCA-d4 (IS) Taurolithocholic Acid-d4 TUDCA-d4 (IS) Tauroursodeoxycholic Acid-d5 TCA-d4 (IS) Taurocholic Acid-d4 Figure S1.
    [Show full text]