DOCSLIB.ORG

Comparative Proteomic Study Reveals 17Β-HSD13 As a Pathogenic Protein in Nonalcoholic Fatty Liver Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Comparative Proteomic Study Reveals 17Β-HSD13 As a Pathogenic Protein in Nonalcoholic Fatty Liver Disease Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease Wen Sua,1, Yang Wangb,c,1, Xiao Jiaa,1, Wenhan Wud, Linghai Lib, Xiaodong Tiand, Sha Lia, Chunjiong Wanga, Huamin Xua, Jiaqi Caoa, Qifei Hana, Shimeng Xub,c, Yong Chenb, Yanfeng Zhonge,f, Xiaoyan Zhangg, Pingsheng Liub,2, Jan-Åke Gustafssonh,2, and Youfei Guana,g,2 aDepartment of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science, Peking University Health Science Center, Beijing, 100191, China; bNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; cUniversity of Chinese Academy of Sciences, Beijing, 100049, China; dDepartment of Surgery, Peking University First Hospital, Beijing, 100044, China; fDepartment of Pathology, Health Science Center and eBeijing Autopsy Center, Peking University, Beijing, 100191, China; gDepartment of Physiology, Shenzhen University Health Science Center, Shenzhen, 518060, China; and hCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204 Contributed by Jan-Åke Gustafsson, June 9, 2014 (sent for review May 24, 2014; reviewed by Yu Huang, Xiong Ruan, and Tianxin Yang) Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive atherosclerosis. In addition to a monolayer of phospholipids, accumulation of lipid droplets (LDs). The aim of this study was to LDs are also covered by many proteins (12), which have been determine the function of 17β-hydroxysteroid dehydrogenase-13 considered to play an important role in the dynamic regulation of (17β-HSD13), one of our newly identified LD-associated proteins in the size and lipid contents of LDs (13). human subjects with normal liver histology and simple steatosis, in The hallmark feature of the pathogenesis of NAFLD is the NAFLD development. LDs were isolated from 21 human liver biop- accumulation of TGs in the liver, which results in large hepatic sies, including 9 cases with normal liver histology (group 1) and 12 LDs (14). Although a number of studies have provided useful cases with simple steatosis (group 2). A complete set of LD-associ- information about the protein composition of LDs in many dif- ated proteins from three liver samples of group 1 or group 2 were ferent species, ranging from bacteria to mammals (12), there has determined by 2D LC-MS/MS. By comparing the LD-associated pro- yet to be a report detailing the proteome of human liver LDs. In tein profiles between subjects with or without NAFLD, 54 up-regu- the present study, we performed a proteomic study of human liver lated and 35 down-regulated LD-associated proteins were found LDs purified from human subjects with or without simple stea- β MEDICAL SCIENCES in NAFLD patients. Among them, 17 -HSD13 represents a previously tosis. We also compared protein profiles of LDs of human livers unidentified LD-associated protein with a significant up-regulation with or without simple fatty liver. Among many differentially in NAFLD. Because the 17β-HSD family plays an important role in β β β expressed proteins, 17 -hydroxysteroid dehydrogenase-13 (17 - lipid metabolism, 17 -HSD13 was selected for validating the proteo- HSD13) represents a previously unidentified human liver LD-as- mic findings and exploring its role in the pathogenesis of NAFLD. sociated protein, which is significantly up-regulated in the hepatic Increased hepatic 17β-HSD13 and its LD surface location were con- LDs of patients with fatty liver and enhances hepatic lipogenesis in firmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus- normal mouse liver and cultured human hepatocytes. mediated hepatic overexpression of human 17β-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase Results in mature sterol regulatory element-binding protein 1 and fatty acid Histological and Morphological Analyses of the Livers of Human synthase levels. The present study reports an extensive set of hu- Subjects With or Without Simple Steatosis. man liver LD proteins and an array of proteins differentially Histological and mor- expressed in human NAFLD. We also identified 17β-HSD13 as a path- phological examination showed typical hepatocellular steatosis ogenic protein in the development of NAFLD. and ballooning, without inflammation and fibrosis in patients lipogenesis | SCDR9 | HSDI7β13 Significance onalcoholic fatty liver disease (NAFLD) has become a major Nonalcoholic fatty liver disease (NAFLD) is a common chronic Nhealth concern worldwide (1). NAFLD comprises a morpho- hepatic disease affecting up to 25% of subjects in the de- logical spectrum of liver lesions ranging from simple triglyceride veloped world, and represents a progressive illness eventually (TG) accumulation in hepatocytes (simple steatosis) to inflam- leading to liver fibrosis and cirrhosis. This study reports an matory and hepatocellular ballooning injury (nonalcoholic stea- extensive set of human liver lipid droplet (LD)-associated pro- teins and an array of proteins differentially expressed in human tohepatitis), eventually leading to fibrosis and cirrhosis (2). NAFLD. We also uncover 17β-hydroxysteroid dehydrogenase-13, NAFLD is a well-documented risk factor for hyperlipidemia (3), a newly identified LD-associated protein, as a pathogenic mole- type 2 diabetes (4), and hepatocarcinoma (5). Histologically, cule in the development of NAFLD. The present study provides NAFLD is characterized by a significant accumulation of lipid a potential link between LD proteins and the pathogenesis of droplets (LDs) (1), subcellular organelles consisting of a neutral hepatic steatosis. lipid core covered by a monolayer of phospholipids and many associated proteins (6–9). LDs provide a temporary storage site Author contributions: W.S., Y.W., X.J., P.L., J.-Å.G., and Y.G. designed research; W.S., Y.W., for accumulated TGs resulting from either enhanced de novo X.J., W.W., L.L., X.T., S.L., C.W., H.X., J.C., Q.H., S.X., Y.C., Y.Z., and X.Z. performed re- synthesis or increased exogenous uptake of fatty acids in hepa- search; P.L., J.-Å.G., and Y.G. contributed new reagents/analytic tools; W.S., Y.W., and X.J. analyzed data; and W.S., Y.W., X.J., P.L., J.-Å.G., and Y.G. wrote the paper. tocytes. Stored TGs in LDs are mobilized for the assembly of Reviewers: Y.H., The Chinese University of Hong Kong; X.R., University College London; very low-density lipoproteins or used for peroxisomal and mi- and T.Y., University of Utah. β tochondrial -oxidation under tight control from multiple nu- The authors declare no conflict of interest. clear transcription factors (10). 1W.S., Y.W., and X.J. contributed equally to this work. An LD is now recognized as an organelle involved in lipid 2To whom correspondence may be addressed. Email: [email protected], [email protected], storage and metabolism, membrane traffic, and signal trans- or [email protected]. duction (11). Increased accumulation of LDs is associated with This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. many metabolic diseases, including obesity, hepatosteatosis, and 1073/pnas.1410741111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1410741111 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 with simple steatosis (SI Appendix, Fig. S1 A–C). Electron mi- Analysis of Liver LD Proteome of Human Subjects Without NAFLD. croscopic examination demonstrated the presence of LDs of To obtain a complete set of LD-associated proteins, three liver various sizes in the cytoplasm of hepatocytes of patients with LD preparations isolated from three human subjects without simple steatosis (SI Appendix, Fig. S1D). Clinical features of all NAFLD were separated using gel electrophoresis and silver stain- patients are summarized in SI Appendix, Table S1. ing, showing very similar protein patterns (SI Appendix,Fig.S2A). LD proteins were then analyzed by 2D LC-MS/MS. A total of 596 Isolation and Characterization of LDs from Human Liver. Human liver proteins were identified in the first preparation, 555 in the second LDs were purified using a modification of a method described preparation, and 501 in the third preparation (SI Appendix,Tables previously (15, 16). The quality of the preparation was first exam- S2–S4). Collectively, a total of 713 proteins were found in three ined by fluorescence microscopy using Nile red staining (Fig. 1A). preparations (SI Appendix,TableS5). LDs stained with Nile red showed spherical structures of various To enhance the validity of the data, only proteins with two or sizes. Consistent with a previous report, the sizes of most LDs more unique peptides and present in all three preparations were ranged between 1 and 3 μm, which is smaller than fat cell LDs and considered to be putative human liver LD proteins (SI Appendix, bigger than LDs from skeletal muscle (17). To assess the quality of Fig. S2B). Overall, we identified 148 proteins, which we consider the isolated LDs, equal amounts of proteins from LD, total mem- to be valid constituents of the human liver LD proteome (SI brane, cytosol (Cyto), and postnuclear supernatant (PNS) fractions Appendix, Table S6). Among these proteins, 66 (44.6%) have were separated by SDS/PAGE. Silver staining revealed that the LD been identified in LDs previously, 26 (17.6%) of which have protein profile was quite different from the profiles of the other previously been reported as possible liver LD proteins in human three fractions (Fig. 1B). To assess the purity of the isolated LDs, hepatoma cell lines and mouse livers (19, 20). The remaining 82 subcellular organelle and compartment-specific markers were tested (55.4%) proteins are, to our knowledge, first described here in the four fractions, which included three LD-specific markers in LDs. [adipose differentiation-related protein (ADRP), acyl-CoA synthe- The 148 LD-associated proteins were categorized into 10 tase long-chain family member 1 (ACSL1), and comparative gene groups based on their functional characteristics and subcellular SI Appendix C identification-58 (CGI-58)], one cytoplasmic marker (GAPDH), locations.
Load more

Recommended publications
  • Three-Dimensional Structure of Holo 3A,20J3-Hydroxysteroid
    Proc. Nati. Acad. Sci. USA Vol. 88, pp. 10064-10068, November 1991 Biochemistry Three-dimensional structure of holo 3a,20j3-hydroxysteroid dehydrogenase: A member of a short-chain dehydrogenase family (x-ray crystaflography/steroid-metabolizing enzyme/dinucleotide-linked oxldoreductase/sterold-protein interaction/sequence and folding homologies) DEBASHIS GHOSH*t, CHARLES M. WEEKS*, PAWEL GROCHULSKI*t, WILLIAM L. DUAX*, MARY ERMAN*, ROBERT L. RIMSAY§, AND J. C. ORR§ *Medical Foundation of Buffalo, 73 High Street, Buffalo, NY 14203; and Memorial University of Newfoundland, St. John's, Newfoundland, Canada AlB 3V6 Communicated by Herbert A. Hauptman, July 18, 1991 (receivedfor review May 14, 1991) ABSTRACT The x-ray structure of a short-chain dehy- the substrate binding regions, offers further insight concern- drogenase, the bacterial holo 3a,20/3-hydroxysteroid dehydro- ing the significance of conserved residues and their possible genase (EC 1.1.1.53), is described at 2.6 A resolution. This roles in substrate specificity and overall enzyme function. enzyme is active as a tetramer and crystallizes with four identical subunits in the asymmetric unit. It has the a/( fold characteristic ofthe dinucleotide binding region. The fold ofthe MATERIALS AND METHODS rest of the subunit, the quarternary structure, and the nature The crystals, grown in the presence of 4 mM NADH, belong ofthe cofactor-enzyme interactions are, however, significantly to the space group P43212 having unit cell dimensions a = different from those observed in the long-chain dehydrogena- 106.2 A and c = 203.8 A and contain one full tetramer (106 ses. The architecture of the postulated active site is consistent kDa) in the asymmetric unit (13).
    [Show full text]
  • 1970Qureshiocr.Pdf (10.44Mb)
    STUDY INVOLVING METABOLISM OF 17-KETOSTEROIDS AND 17-HYDROXYCORTICOSTEROIDS OF HEALTHY YOUNG MEN DURING AMBULATION AND RECUMBENCY A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN NUTRITION IN THE GRADUATE DIVISION OF THE TEXAS WOI\IIAN 'S UNIVERSITY COLLEGE OF HOUSEHOLD ARTS AND SCIENCES BY SANOBER QURESHI I B .Sc. I M.S. DENTON I TEXAS MAY I 1970 ACKNOWLEDGMENTS The author wishes to express her sincere gratitude to those who assisted her with her research problem and with the preparation of this dissertation. To Dr. Pauline Beery Mack, Director of the Texas Woman's University Research Institute, for her invaluable assistance and gui­ dance during the author's entire graduate program, and for help in the preparation of this dissertation; To the National Aeronautics and Space Administration for their support of the research project of which the author's study is a part; To Dr. Elsa A. Dozier for directing the author's s tucly during 1969, and to Dr. Kathryn Montgomery beginning in early 1970, for serving as the immeclia te director of the author while she was working on the completion of the investic;ation and the preparation of this dis- sertation; To Dr. Jessie Bateman, Dean of the College of Household Arts and Sciences, for her assistance in all aspects of the author's graduate program; iii To Dr. Ralph Pyke and Mr. Walter Gilchrist 1 for their ass is­ tance and generous kindness while the author's research program was in progress; To Mr. Eugene Van Hooser 1 for help during various parts of her research program; To Dr.
    [Show full text]
  • The Effects of Exogenous ACTH on 5-3B-Hydroxysteroid Dehydrogenase Activity in the Embryonic Avian Adrenal Gland
    Loyola University Chicago Loyola eCommons Master's Theses Theses and Dissertations 1968 The Effects of Exogenous ACTH on 5-3b-hydroxysteroid Dehydrogenase Activity in the Embryonic Avian Adrenal Gland Grover Charles Ericson Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_theses Part of the Medicine and Health Sciences Commons Recommended Citation Ericson, Grover Charles, "The Effects of Exogenous ACTH on 5-3b-hydroxysteroid Dehydrogenase Activity in the Embryonic Avian Adrenal Gland" (1968). Master's Theses. 2264. https://ecommons.luc.edu/luc_theses/2264 This Thesis is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Master's Theses by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 1968 Grover Charles Ericson THE EFFECTS OF EXOGENOUS ACTH ON d -JB-HYDROXYSTEROID DEHYDROGENASE ACTIVITY IN THE EMBRYONIC AVIAN ADRENAL GLAND by Grover Charles Ericson A The.is Submitted to the Faculty ot the Graduate School of La.vo1. University in Partial Fulfillment ot the Requirements for the Degree ot Master ot Science February 1968 BIOGRAPHY Grover Charles Ericson was born in Oak Park, D.linois, on February 17. 1941. He •• graduated f'rom the Naperville COIIUlIW1ity High School, Naperville. D.l1nois in June, 19.59. He entered North Central College, Naperville. Illinois, in September, 19.59, and was awarded the Bachelor of Arts degree in June, 1964. While attending North Central College.
    [Show full text]
  • A Thesis Entitled "APPLICATIONS of GAS CHROMATOGRAPHY
    A Thesis entitled "APPLICATIONS OF GAS CHROMATOGRAPHY - MASS SPECTROMETRY IN STEROID CHEMISTRY" Submitted in part fulfilment of the requirements for admittance to the degree of Doctor of Philosophy in The University of Glasgow by T.A. Baillie, B.Sc. University of Glasgow 1973. ProQuest Number: 11017930 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 11017930 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ACKNOWLEDGEMENTS I would like to express my sincere thanks to Dr. C.3.W. Brooks for his guidance and encouragement at all times, and to Professors R.A. Raphael, F.R.S., and G.W. Kirby, for the opportunity to carry out this research. Thanks are also due to my many colleagues for useful discussions, and in particular to Dr. B.S. Middleditch who was associated with me in the work described in Section 3 of this thesis. The work was carried out during the tenure of an S.R.C. Research Studentship, which is gratefully acknowledged. Finally, I would like to thank Miss 3.H.
    [Show full text]
  • Structural Basis for Human Sterol Isomerase in Cholesterol Biosynthesis and Multidrug Recognition
    ARTICLE https://doi.org/10.1038/s41467-019-10279-w OPEN Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition Tao Long 1, Abdirahman Hassan 1, Bonne M Thompson2, Jeffrey G McDonald1,2, Jiawei Wang3 & Xiaochun Li 1,4 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, 1234567890():,; oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacolo- gically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder. 1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. 4 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
    [Show full text]
  • Evolution of 17Beta-Hydroxysteroid Dehydrogenases and Their Role in Androgen, Estrogen and Retinoid Action
    UC San Diego UC San Diego Previously Published Works Title Evolution of 17beta-Hydroxysteroid Dehydrogenases and Their Role in Androgen, Estrogen and Retinoid Action Permalink https://escholarship.org/uc/item/1md640v5 Journal Molecular and Cellular Endocrinology, 171 Author Baker, Michael E Publication Date 2001 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Molec ular and Cellular Endocrinol ogy vol. 171, pp. 211 -215, 2001. Evolution of 17 -Hydroxysteroid Dehydrogenases and Their Role in Androgen, Estrogen and Retinoid Action Michael E. Baker Department of Medicine, 0823 University of California, San Diego 950 0 Gilman Drive La Jolla, CA 92093 -0823 phone: 858 -534 -8317 fax: 858 -822 -0873 e-mail: [email protected] Abstract. 17 -hydroxysteroid dehydrogenases (17 -HSDs) regulate androgen and estrogen concentrations in mammals. By 1995, four distinct enzymes with 17 -HSD activity had been identified: 17 -HSD -types 1 and 3, which in vivo are NADPH -dependent reductases; 17 -HSD - types 2 and 4, which in vivo are NAD +-dependent oxidases. Since then six additional enzymes with 17 -HSD activity have been isolated from mammal s. With the exception of 17 -HSD –type 5, which belongs to the aldoketo -reductase (AKR) family, these 17 -HSDs belong to the short chain dehydrogenases/reductases (SDR) family. Several 17 -HSDs appear to be examples of convergent evolution. That is, 17 -HSD activity arose several times from different ancestors. Some 17 -HSDs share a common ancestor with retinoid oxido -reductases and have retinol dehydrogenase activity. 17 -HSD -types 2, 6 and 9 appear to have diverged from ancestral retinoid dehydrogenas es early in the evolution of deuterostomes during the Cambrian, about 540 million years ago.
    [Show full text]
  • Nomenclature of Steroids
    Pure&App/. Chern.,Vol. 61, No. 10, pp. 1783-1822,1989. Printed in Great Britain. @ 1989 IUPAC INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY and INTERNATIONAL UNION OF BIOCHEMISTRY JOINT COMMISSION ON BIOCHEMICAL NOMENCLATURE* NOMENCLATURE OF STEROIDS (Recommendations 1989) Prepared for publication by G. P. MOSS Queen Mary College, Mile End Road, London El 4NS, UK *Membership of the Commission (JCBN) during 1987-89 is as follows: Chairman: J. F. G. Vliegenthart (Netherlands); Secretary: A. Cornish-Bowden (UK); Members: J. R. Bull (RSA); M. A. Chester (Sweden); C. LiCbecq (Belgium, representing the IUB Committee of Editors of Biochemical Journals); J. Reedijk (Netherlands); P. Venetianer (Hungary); Associate Members: G. P. Moss (UK); J. C. Rigg (Netherlands). Additional contributors to the formulation of these recommendations: Nomenclature Committee of ZUB(NC-ZUB) (those additional to JCBN): H. Bielka (GDR); C. R. Cantor (USA); H. B. F. Dixon (UK); P. Karlson (FRG); K. L. Loening (USA); W. Saenger (FRG); N. Sharon (Israel); E. J. van Lenten (USA); S. F. Velick (USA); E. C. Webb (Australia). Membership of Expert Panel: P. Karlson (FRG, Convener); J. R. Bull (RSA); K. Engel (FRG); J. Fried (USA); H. W. Kircher (USA); K. L. Loening (USA); G. P. Moss (UK); G. Popjiik (USA); M. R. Uskokovic (USA). Correspondence on these recommendations should be addressed to Dr. G. P. Moss at the above address or to any member of the Commission. Republication of this report is permitted without the need for formal IUPAC permission on condition that an acknowledgement, with full reference together with IUPAC copyright symbol (01989 IUPAC), is printed.
    [Show full text]
  • Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deficiency Abhishek Thakur 1, Subhash C
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector J Acupunct Meridian Stud 2016;9(3):109e117 Available online at www.sciencedirect.com Journal of Acupuncture and Meridian Studies journal homepage: www.jams-kpi.com REVIEW ARTICLE Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deficiency Abhishek Thakur 1, Subhash C. Mandal 2, Sugato Banerjee 1,* 1 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India 2 Division of Pharmacognosy, Pharmacognosy and Phytotherapy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India Available online 17 February 2016 Received: Sep 2, 2015 Abstract Revised: Jan 24, 2016 A predominant number of diseases affecting women are related to female hormones. In Accepted: Jan 28, 2016 most of the cases, these diseases are reported to be associated with menstrual problems. These diseases affect female reproductive organs such as the breast, uterus, and ovaries. KEYWORDS Estrogen is the main hormone responsible for the menstrual cycle, so irregular menstru- acupuncture; ation is primarily due to a disturbance in estrogen levels. Estrogen imbalance leads to estrogen; various pathological conditions in premenopausal women, such as endometriosis, breast natural compounds cancer, colorectal cancer, prostate cancer, poly cysts, intrahepatic cholestasis of preg- nancy, osteoporosis, cardiovascular diseases, obesity, etc. In this review, we discuss com- mon drug targets and therapeutic strategies, including acupuncture and compounds of natural origin, for the treatment of diseases caused by estrogen deficiency. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any me- dium, provided the original work is properly cited.
    [Show full text]
  • Physiological and Biochemical Aspects of 17Β-Hydroxysteroid Dehydrogenase Type 2 and 3
    Physiological and Biochemical Aspects of 17β-Hydroxysteroid Dehydrogenase Type 2 and 3 Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Roger Thomas Engeli aus Sulgen (TG), Schweiz Basel, 2017 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung-Nicht kommerziell 4.0 International Lizenz. Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Alex Odermatt und Prof. Dr. Rik Eggen Basel, den 20.06.2017 ________________________ Dekan Prof. Dr. Martin Spiess 2 Table of Contents Table of Contents ............................................................................................................................... 3 Abbreviations ..................................................................................................................................... 4 1. Summary ........................................................................................................................................ 6 2. Introduction ................................................................................................................................... 8 2.1 Steroid Hormones ............................................................................................................................... 8 2.2 Human Steroidogenesis....................................................................................................................
    [Show full text]
  • Characterization of Steroid-17,20-Desmolase and 20Α- Hydroxysteroid Dehydrogenase from Clostridium Scindens
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 1989 CHARACTERIZATION OF STEROID-17,20-DESMOLASE AND 20α- HYDROXYSTEROID DEHYDROGENASE FROM CLOSTRIDIUM SCINDENS Amy Elizabeth Krafft Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Microbiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/4980 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. School of Basic Health Sciences Virginia Commonwealth University This is to certify that the thesis or dissertation prepared by Amy Elizabeth Krafft entitled "The Characterization of steroid-17,20-Desmolase and 20«­ Hydroxysteroid Dehydrogenase from Clostridium scindens" has been approved by her committee as satisfactory completion of the thesis or dissertation requirement for the degree of Doctor of Philosophy. CHARACTERIZATION OF STEROID-17,20-DESMOLASE AND 20a-HYDROTfSTEROID DEfffDROGENASE FROM CLOSTRIDITJM SCINDENS A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By Amy Elizabeth Krafft B.S., Mary Washington College, 1977 Director: Dr. Phillip B. Hylemon, Professor, Department of Microbiology and Immunology Virginia Commonwealth University Richmond, Virginia May, 1989 ii Acknowledgements I wish to thank Dr . Phillip Hylemon for all of the support he has given me during my graduate training. I also would like to thank my committee members for their guidance: Drs . Francis Macrina, Darrell Peterson, Thomas Huff, and Charles Schwartz .
    [Show full text]
  • Ágnes Berényi Anticancer Effects of Estrone Derivatives And
    University of Szeged Doctoral School of Pharmaceutical Sciences Pharmacology, Biopharmacy and Clinical Therapy Ph.D program Program leader: George Falkay Ph.D., D.Sc. Department of Pharmacodynamics and Biopharmacy Supervisor: Dr. habil. István Zupkó Ph.D. Ágnes Berényi Anticancer effects of estrone derivatives and nonsteroidal 17β- hydroxysteroid dehydrogenase type 1 inhibitors Exam board: Chairman: George Falkay Ph.D., D.Sc. Members: Zoltán Havass Ph.D. Ágnes Végh Ph.D., D.Sc. Reviewer broad: Chairman: Imre Máthé Ph.D., D.Sc. Reviewers: József Molnár Ph.D., D.Sc. Pál Perjési Ph.D. Member: Géza Regdon Ph.D. Secretary: Zsolt Szakonyi Ph.D. INTRODUCTION Cancer is a major health problem and leading disease in many countries worldwide. Accordance to the survey lung cancer is the leading cancer type of men’s while breast cancer of women’s. Growth control of the tumors is a very complex multifactorial process and characterized with dedifferentiation and uncontrolled cellular proliferation. Natural steroid products and their synthetic analogs are intensively investigated in order to describe and exploit their anticancer capacity, thus it could be considered a basic source of innovative drugs. Therefore, steroidal-type structures with different function group may suggest starting structures for novel synthetic antiproliferative drugs. Diosgenin and many related steroidal alkaloids exhibit potent anticancer effects. The most intensively investigated estrane is an endogenous estradiol metabolite, 2-methoxyestradiol, which does not exhibit hormonal activity, but seems to be highly effective against a broad range of cancer cell lines. The most important estrogen, 17β-estradiol, is involved in many hormone-dependent proliferative disorders in humans, including cancers of gynecological origin and endometriosis.
    [Show full text]
  • Estradiol RenE Maltais, Diana Ayan, and Donald Poirier*
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central LETTER pubs.acs.org/acsmedchemlett Crucial Role of 3-Bromoethyl in Removing the Estrogenic Activity of 17β-HSD1 Inhibitor 16β-(m-Carbamoylbenzyl)estradiol Rene Maltais, Diana Ayan, and Donald Poirier* Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ (CHUL) À Research Center and Laval University, Quebec (Quebec) G1V 4G2, Canada bS Supporting Information ABSTRACT: 17β-Hydroxysteroid dehydrogenase type 1 (17 β-HSD1) represents a promising therapeutic target for breast cancer treatment. To reduce the undesirable estrogenic activity of potent 17β-HSD1 inhibitor 16β-(m-carbamoylbenzyl)- estradiol (1) (IC50 = 27 nM), a series of analogues with a small functionalized side chain at position 3 were synthesized and tested. The 3-(2-bromoethyl)-16β-(m-carbamoylbenzyl)-estra- 1,3,5(10)-trien-17β-ol (5) was found to be a potent inhibitor (IC50 = 68 nM) for the transformation of estrone (E1) into estradiol (E2) and, most importantly, did not stimulate the proliferation of estrogen-sensitive MCF-7 cells, suggesting no estrogenic activity. From these results, the crucial role of a bromoalkyl side chain at carbon 3 was identified for the first time. Thus, this new inhibitor represents a good candidate with an interesting profile suitable for further studies including pharmacokinetic and in vivo studies. KEYWORDS: Steroid, estrogen, hormone, enzyme inhibitor, 17β-hydroxysteroid dehydrogenase, cancer ydroxysteroid dehydrogenase type
    [Show full text]