DOCSLIB.ORG

Interactions Between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interactions Between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases Journal of Lipids Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases Guest Editors: David Q.-H. Wang, Brent A. Neuschwander-Tetri, Piero Portincasa, and William M. Pandak Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases Journal of Lipids Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases Guest Editors: David Q.-H. Wang, Brent A. Neuschwander-Tetri, Piero Portincasa, and William M. Pandak Copyright © 2012 Hindawi Publishing Corporation. All rights reserved. This is a special issue published in “Journal of Lipids.” All articles are open access articles distributed under the Creative Commons At- tribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Maurizio Averna, Italy Xian-Cheng Jiang, USA Robert Salomon, USA Rhoderick Brown, USA Gerhard M. Kostner, Austria Gerd Schmitz, Germany Teodor Brumeanu, USA RumianaKoynova,USA Aleksander F. Sikorski, Poland Angel Catala, Argentina Arkadiusz Kozubek, Poland Roland Verhe,´ Belgium Michael A. Crawford, UK Stan Kubow, Canada Rosemary Lee Walzem, USA J. F. Glatz, The Netherlands M. Lagarde, France Philip W. Wertz, USA Bruce Griffin, UK Clifford A. Lingwood, Canada W. Gibson Wood, USA J. A. Hamilton, USA Shinichi Oikawa, Japan Xuebing Xu, Denmark Xianlin Han, USA Sampath Parthasarathy, USA Teruyoshi Yanagita, Japan Walter M. Holleran, USA Javier S. Perona, Spain Zemin Yao, Canada Akihiro Inazu, Japan Alessandro Prinetti, Italy David J. A. Jenkins, Canada U. Ravnskov, Sweden Contents Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases, David Q.-H. Wang, Brent A. Neuschwander-Tetri, Piero Portincasa, and William M. Pandak Volume 2012, Article ID 560715, 2 pages A Pleiotropic Role for the Orphan Nuclear Receptor Small Heterodimer Partner in Lipid Homeostasis and Metabolic Pathways, Gabriella Garruti, Helen H.Wang, Leonilde Bonfrate, Ornella de Bari, David Q.-H.Wang, and Piero Portincasa Volume 2012, Article ID 304292, 22 pages Nuclear Receptor Variants in Liver Disease,RomanMullenbach,¨ Susanne N. Weber, and Frank Lammert Volume 2012, Article ID 934707, 12 pages Fatty Acid Oxidation and Cardiovascular Risk during Menopause: A Mitochondrial Connection?, Paulo J. Oliveira, Rui A. Carvalho, Piero Portincasa, Leonilde Bonfrate, and Vilma A. Sardao Volume 2012, Article ID 365798, 12 pages Nuclear Receptors in Nonalcoholic Fatty Liver Disease, Jorge A. Lopez-Vel´ azquez,´ Luis D. Carrillo-Cordova,´ Norberto C. Chavez-Tapia,´ Misael Uribe, and Nahum Mendez-S´ anchez´ Volume 2012, Article ID 139875, 10 pages Non-Alcoholic Fatty Liver Disease: The Bile Acid-Activated Farnesoid X Receptor as an Emerging Treatment Target, Michael Fuchs Volume 2012, Article ID 934396, 8 pages Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease, Ornella de Bari, Brent A. Neuschwander-Tetri, Min Liu, Piero Portincasa, and David Q.-H. Wang Volume 2012, Article ID 302847, 16 pages Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation, Mary Carmen Vazquez,´ Attilio Rigotti, and Silvana Zanlungo Volume 2012, Article ID 547643, 7 pages Bile Acid Signaling in Liver Metabolism and Diseases, Tiangang Li and John Y. L. Chiang Volume 2012, Article ID 754067, 9 pages Hindawi Publishing Corporation Journal of Lipids Volume 2012, Article ID 560715, 2 pages doi:10.1155/2012/560715 Editorial Interactions between Bile Acids and Nuclear Receptors and Their Effects on Lipid Metabolism and Liver Diseases David Q.-H. Wang,1 Brent A. Neuschwander-Tetri,2 Piero Portincasa,3 and William M. Pandak4 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, Saint Louis University School of Medicine, 1100 S. Grand Boulevard, St. Louis, MO 63104, USA 2 Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 3635 Vista Avenue, St. Louis, MO 63110, USA 3 Clinica Medica “A. Murri”, Department of Interdisciplinary Medicine (DIM), University of Bari School of Medicine, Policlinico Hospital, Piazza G. Cesare 11, 70124 Bari, Italy 4 Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University Health Sciences Center & Veterans Affairs Medical Center, P.O. Box 980341, Richmond, VA 23298, USA Correspondence should be addressed to David Q.-H. Wang, [email protected] Received 15 January 2012; Accepted 15 January 2012 Copyright © 2012 David Q.-H. Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In this special issue of Journal of Lipids, we acknowledge the lipid metabolism. Besides their detergent properties and key contributionsbyseveralexpertsoffering timely perspectives physiological functions, bile acids are also acting as potent on the complex interactions between bile acids and nuclear metabolic regulators of glucose and lipid homeostasis. The receptors (NRs) on lipid metabolism and liver diseases at identification of bile acid-activated nuclear receptor farne- different levels and contexts in the body. soid X receptor (FXR) and cell surface G-protein-coupled NRs are found within the interior of cells and are defined receptor TGR5 has significantly advanced our understanding as ligand-activated transcriptional regulators of several key on how bile acid signaling regulates cellular metabolism in aspects of body physiology and pathophysiology. NRs regu- health and disease. Thus, novel therapeutic strategies can be late gene transcription through interaction with cellular envisioned which target bile acid metabolism for the treat- coactivators and corepressors. In the liver, NRs play a key role ment of metabolic disorders such as obesity, insulin resist- in a large variety of metabolic processes such as cholesterol, ance, and the metabolic syndrome. bile acid, fatty acid, and glucose homeostasis, as well as drug NRs comprise one of the most abundant classes of tran- disposition. Also, additional critical processes involving the scriptional regulators of metabolic diseases and have pathophysiology of liver diseases—inflammation and fibro- emerged as promising pharmaceutical targets. The paper by sis, regeneration, cell differentiation, and tumor formation— G. Garruti et al. deals with the myriad roles of small het- are modulated by NRs. Of note, NRs are or might soon be- erodimer partner (SHP), a unique orphan nuclear receptor come drug targets. Despite the huge accumulation of knowl- lacking a DNA-binding domain, but containing a putative edge in the field, the true comprehension of interactions ligand-binding domain. About half of mammalian NRs and between bile acids and NRs on lipid metabolism and hepato- several transcriptional coregulators can interact with SHP. biliary diseases has remained elusive. Thus continuous efforts SHP is a transcriptional regulator affecting multiple key bi- are being made to understand the molecular functions of ological functions and metabolic processes including choles- NRs, the significance of bile acid-controlled signaling path- terol, bile acid, and fatty acid metabolism, as well as repro- ways, and interactions of NRs on a number of metabolic and ductive biology and glucose-energy homeostasis. In humans, hepatic diseases. studies are emerging on the association of SHP genetic The paper of T. Li and Y. L. Chiang is focused on the role variation with birth weight, high body mass index, obesity, of bile acid signaling in the regulation of glucose and insulin resistance, and diabetes. Future research must be 2 Journal of Lipids focused on synthetic ligands acting on SHP as a potential crucial steps include fat storage, export, uptake, oxidation, therapeutic target in a series of metabolic abnormalities. and lipolysis. A whole family of NRs is targeted by many One important issue in lipidology is the understanding ligands controlling lipid metabolism including fatty acids, of the molecular mechanisms whereby cholesterol and fatty oxysterols, and lipophilic molecules. Understanding the acids are absorbed from the intestine and are transported molecular mechanisms underlying the involvement of NRs to the liver. The cholesterol absorption inhibitor ezetimibe in the pathogenesis of NAFLD may, therefore, offer targets can significantly reduce plasma total and LDL cholesterol for the development of new treatments of one of the most concentrations by inhibiting the Niemann-Pick C1-like 1 frequent chronic liver diseases worldwide. protein (NPC1L1), an intestinal sterol influx transporter that In their paper, R. Mullenbach¨ et al. provided an update can actively facilitate the uptake of cholesterol for intestinal on genetic variants of NRs involved in regulating important absorption. The paper by O. de Bari et al. emphasizes the aspects of liver metabolism. One such aspect is the applica- novel concept that, ezetimibe treatment also induces a com- tion of NRs in genetic diagnosis of monogenic (Mendelian) plete resistance to two frequent metabolic abnormalities, liver diseases and their uses in clinical diagnosis. Moreover, namely, cholesterol gallstones and nonalcoholic fatty liver a role
Load more

Recommended publications
  • Functional Analysis of the Homeobox Gene Tur-2 During Mouse Embryogenesis
    Functional Analysis of The Homeobox Gene Tur-2 During Mouse Embryogenesis Shao Jun Tang A thesis submitted in conformity with the requirements for the Degree of Doctor of Philosophy Graduate Department of Molecular and Medical Genetics University of Toronto March, 1998 Copyright by Shao Jun Tang (1998) National Library Bibriothèque nationale du Canada Acquisitions and Acquisitions et Bibiiographic Services seMces bibliographiques 395 Wellington Street 395, rue Weifington OtbawaON K1AW OttawaON KYAON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence alIowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distri%uteor sell reproduire, prêter' distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Functional Analysis of The Homeobox Gene TLr-2 During Mouse Embryogenesis Doctor of Philosophy (1998) Shao Jun Tang Graduate Department of Moiecular and Medicd Genetics University of Toronto Abstract This thesis describes the clonhg of the TLx-2 homeobox gene, the determination of its developmental expression, the characterization of its fiuiction in mouse mesodem and penpheral nervous system (PNS) developrnent, the regulation of nx-2 expression in the early mouse embryo by BMP signalling, and the modulation of the function of nX-2 protein by the 14-3-3 signalling protein during neural development.
    [Show full text]
  • Ptf1a/Rbpj Complex Inhibits Ganglion Cell Fate and Drives the Specification of All Horizontal Cell Subtypes in the Chick Retina
    Ptf1a/Rbpj complex inhibits ganglion cell fate and drives the specification of all horizontal cell subtypes in the chick retina. Elise Lelièvre, Monkol Lek, Henrik Boije, L. Houille-Vernes, Valérie Brajeul, A. Slembrouck, Jérôme Roger, José-Alain Sahel, Jean-Marc Matter, Florian Sennlaub, et al. To cite this version: Elise Lelièvre, Monkol Lek, Henrik Boije, L. Houille-Vernes, Valérie Brajeul, et al.. Ptf1a/Rbpj complex inhibits ganglion cell fate and drives the specification of all horizontal cell subtypes in the chick retina.: Ptf1a in chick retinal development. Developmental Biology, Elsevier, 2011, 358 (2), pp.296-308. 10.1016/j.ydbio.2011.07.033. inserm-00614775 HAL Id: inserm-00614775 https://www.hal.inserm.fr/inserm-00614775 Submitted on 16 Aug 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Ptf1a/Rbpj complex inhibits ganglion cell fate and drives the specification of all horizontal cell subtypes in the chick retina. 1,2,3,4,5 6 6 2,4,5 2,4,5 E.C. Lelièvre , M. Lek , H. Boije , L. Houille-Verne s , V. Brajeul , A. Slembrouck2,4,5, J.E. Roger4, J. Sahel2,4,5, J.M.
    [Show full text]
  • Modulation of the Activity of a Key Metabolic Regulator Small Heterodimer Partner by Post-Translational Modifications
    MODULATION OF THE ACTIVITY OF A KEY METABOLIC REGULATOR SMALL HETERODIMER PARTNER BY POST-TRANSLATIONAL MODIFICATIONS BY DEEPTHI KANAMALURU DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2011 Urbana, Illinois Doctoral Committee: Associate Professor Jongsook Kim Kemper, Chair Professor David J. Shapiro Professor Milan K. Bagchi Assistant Professor Lin-Feng Chen Abstract Small Heterodimer Partner (SHP, NR0B2), a member of the nuclear receptor superfamily, is an orphan receptor that lacks a DNA binding domain but contains a putative ligand binding domain. SHP forms non-functional heterodimers with DNA binding transcriptional factors and, thereby, functions as a transcriptional corepressor in diverse biological processes, including cellular metabolism, cell proliferation, apoptosis, and sexual maturation. Of these reported functions of SHP, maintaining cholesterol and bile acid levels by negative feedback regulation of hepatic conversion of cholesterol to bile acids is well established. Cholesterol is essential in many biological activities in mammalian cells. Conversion of hepatic cholesterol into bile acids is a major pathway to eliminate cholesterol from the body. However, excess amounts of cholesterol and bile acids are pathogenic. Therefore, the levels of cholesterol and bile acids need to be tightly regulated. Cholesterol 7α-hydroxylase (CYP7A1), a liver specific P450 enzyme, is the first and rate-limiting enzyme in this process. Increased levels of bile acids repress transcription of CYP7A1 in a feedback manner. In response to elevated bile acid levels, the nuclear bile acid receptor Farnesoid X Receptor (FXR) increases the transcription of SHP.
    [Show full text]
  • Dynamic Transcriptomic Profiles of Zebrafish Gills in Response to Zinc
    Zheng et al. BMC Genomics 2010, 11:548 http://www.biomedcentral.com/1471-2164/11/548 RESEARCH ARTICLE Open Access Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion Dongling Zheng1,4, Peter Kille2, Graham P Feeney2, Phil Cunningham1, Richard D Handy3, Christer Hogstrand1* Abstract Background: Zinc deficiency is detrimental to organisms, highlighting its role as an essential micronutrient contributing to numerous biological processes. To investigate the underlying molecular events invoked by zinc depletion we performed a temporal analysis of transcriptome changes observed within the zebrafish gill. This tissue represents a model system for studying ion absorption across polarised epithelial cells as it provides a major pathway for fish to acquire zinc directly from water whilst sharing a conserved zinc transporting system with mammals. Results: Zebrafish were treated with either zinc-depleted (water = 2.61 μgL-1; diet = 26 mg kg-1) or zinc-adequate (water = 16.3 μgL-1; diet = 233 mg kg-1) conditions for two weeks. Gill samples were collected at five time points and transcriptome changes analysed in quintuplicate using a 16K oligonucleotide array. Of the genes represented the expression of a total of 333 transcripts showed differential regulation by zinc depletion (having a fold-change greater than 1.8 and an adjusted P-value less than 0.1, controlling for a 10% False Discovery Rate). Down-regulation was dominant at most time points and distinct sets of genes were regulated at different stages. Annotation enrichment analysis revealed that ‘Developmental Process’ was the most significantly overrepresented Biological Process GO term (P = 0.0006), involving 26% of all regulated genes.
    [Show full text]
  • Discovering Mechanisms That Regulate Beta-Cell Neogenesis
    DISCOVERING MECHANISMS THAT REGULATE BETA-CELL NEOGENESIS AND PROLIFERATION by Hannah Elizabeth Edelman A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland November 2018 ABSTRACT In both Type I and Type II diabetes, a loss of functioning beta cells results in an inability to produce insulin effectively to regulate blood glucose. Current treatments have a variety of problems including insulin-dependence, donor scarcity, comorbidities, and cost. We are interested in inducing the body to produce its own beta cells endogenously by either neogenesis from progenitors or proliferation of existing beta cells. From previous work, we know that the transcription factor Sox9b plays an important role in the identity of endocrine progenitor cells in the zebrafish pancreas, known as centroacinar cells (CACs), that contribute to regeneration of beta cells. Since humans also have CACs but do not regenerate efficiently, we wanted to understand the downstream targets of Sox9b/SOX9 and their role in the biology of CACs. Using RNA-seq and ChIP-seq in PANC-1 cells we were able to find direct targets of SOX9, including the interesting candidate EPCAM, to follow up on. For assessing beta-cell proliferation, we knew from a previous screen that selective serotonin reuptake inhibitors (SSRIs) can induce beta-cell proliferation in the larval zebrafish. We hypothesized that innervation of the principal islet was responsible for this serotonergic signaling to the pancreas. Using imaging of a variety of transgenic lines, we established that innervation of the islet occurs by 4 days post fertilization and that the sox10 mutant zebrafish has a reduced amount of this innervation.
    [Show full text]
  • Forkhead Transcription Factors and Ageing
    Oncogene (2008) 27, 2351–2363 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc REVIEW Forkhead transcription factors and ageing L Partridge1 and JC Bru¨ ning2 1Institute of Healthy Ageing, GEE, London, UK; 2Department of Mouse Genetics and Metabolism, Institute for Genetics University of Cologne, Cologne, Germany Mutations in single genes and environmental interventions Forkhead transcription factors are turning out to play can extend healthy lifespan in laboratory model organi- a key role in invertebrate models ofextension ofhealthy sms. Some of the mechanisms involved show evolutionary lifespan by single-gene mutations, and evidence is conservation, opening the way to using simpler inverte- mounting for their importance in mammals. Forkheads brates to understand human ageing. Forkhead transcrip- can also play a role in extension oflifespanby dietary tion factors have been found to play a key role in lifespan restriction, an environmental intervention that also extension by alterations in the insulin/IGF pathway and extends lifespan in diverse organisms (Kennedy et al., by dietary restriction. Interventions that extend lifespan 2007). Here, we discuss these findings and their have also been found to delay or ameliorate the impact of implications. The forkhead family of transcription ageing-related pathology and disease, including cancer. factors is characterized by a type of DNA-binding Understanding the mode of action of forkheads in this domain known as the forkhead box (FOX) (Weigel and context will illuminate the mechanisms by which ageing Jackle, 1990). They are also called winged helix acts as a risk factor for ageing-related disease, and could transcription factors because of the crystal structure lead to the development of a broad-spectrum, preventative ofthe FOX, ofwhich the forkheadscontain a medicine for the diseases of ageing.
    [Show full text]
  • Generation of Retinal Neurons: Focus on the Proliferation And
    "They misunderestimated me" George W Bush (2000) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Edqvist, P.H.D., Lek, M., Boije, H., Lindbäck, S.M., Hallböök, F. (2008) Axon-bearing and axon-less horizontal cell subtypes are generated consecutively during chick retinal development from progenitors that are sensitive to follistatin. BMC Developmental Biology, 8:46-67 II Boije, H., Edqvist, P.H.D., Hallböök, F. (2009) Horizontal cell progenitors arrest in G2-phase and undergo terminal mitosis on the vitreal side of the chick retina. Developmental Biology, 330: 105-113 III Fard, S.S., Boije, H., Hallböök, F. (2011) The terminal mitosis of chicken retinal horizontal cells is preceded by a G2-phase arrest that relies on the cyclin B1-Cdk1 complex but is independent of DNA damage. (Submitted to The Journal of Neuroscience) IV Boije, H., Edqvist, P.H., Hallböök, F. (2008) Temporal and spatial expression of transcription factors FoxN4, Ptf1a, Prox1, Isl1 and Lim1 mRNA in the developing chick retina. Gene Expression Patterns, 8:117-123 V Lelièvre, E., Lek, M., Boije, H., Houille, L., Brajeul, V., Slembrouck, A., Sahel, J., Matter, J.M., Sennlaub, F., Hallböök, F., Goureau, O., Guillonneau, X. (2011) Ptf1a/Rbpj complex inhibits ganglion cell fate by downregulating Atoh7 and drives the specification of all horizontal cell subtypes in the chick retina. (Submitted to Developmental Biology) VI Boije, H., Fard, S.S., Ring, H., Hallböök, F. (2011) FoxN4 is sufficient for commitment to the retinal horizontal cell fate and is able to instigate differentiation programs in neural progenitors.
    [Show full text]
  • Molecular Cloning, Promoter Analysis and Expression Profiles of the Sox3 Gene in Japanese Flounder, Paralichthys Olivaceus
    Supplementary Materials: Molecular Cloning, Promoter Analysis and Expression Profiles of the sox3 Gene in Japanese Flounder, Paralichthys olivaceus Jinning Gao, Peizhen Li, Wei Zhang, Zhigang Wang, Xubo Wang and Quanqi Zhang Figure S1. Multiple alignment of Sox3 proteins in different species. All the sequences of Sox3 homologues were retrieved from NCBI and the Ensemble database. The GenBank accession numbers or Ensembl IDs are as follows: P. olivaceus (Paralichthys olivaceus), KR108248; X.maculatus (Xiphophorus maculatus), ENSXMAG00000019515; C.semilaevis (Cynoglossus semilaevis), XP_008324981.1; O.latipes (Oryzias latipes), NP_001098234.1; O.niloticus (Oreochromis niloticus), ENSONIG00000020861; G.aculeatus (Gasterosteus aculeatus), ENSGACG00000017181; D.rerio (Danio rerio), NP_001001811.2; G.morhua (Gadus morhua), ENSGMOG00000020190; L.oculatus (Lepisosteus oculatus), ENSLOCG00000017493; A.mexicanus (Astyanax mexicanus), ENSAMXG00000025368; G.gallus (Gallus gallus), NP_989526.1; H.sapiens (Homo sapiens), NP_005625.2. The HMG box characteristic of Sox proteins are framed and the specificity amino acids in HMG box domain are indicated with asterisks. Gaps (-) are introduced in the sequences to optimize the alignment. The percentage identities of the Japanese flounder Sox3 to its homologues are represented at the end of the sequences. S1 Table S1. Search results using MatInspector program from genomatic software suite. Matrix Matrix Anchor Detailed Family Information Matrix Detailed Matrix Information Strand Sequence Family Sim Position
    [Show full text]
  • Novel Mineralocorticoid Receptor Mechanisms Regulate Cardiac Tissue Inflammation in Male Mice
    246 2 246:2 RESEARCH Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice Gregory S Y Ong1,2,3,4, Timothy J Cole5, Gregory H Tesch6,7, James Morgan1,2, Jennifer K Dowling1,8, Ashley Mansell1,2, Peter J Fuller1,2 and Morag J Young1,2,* 1Hudson Institute of Medical Research, Clayton, Victoria, Australia 2Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia 3Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Murdoch, Western Australia, Australia 4Department of General Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 5Department of Biochemistry, Monash University, Clayton, Victoria, Australia 6Department of Medicine, Monash University, Clayton, Victoria, Australia 7Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia 8Royal College of Surgeons in Ireland, Dublin, Ireland Correspondence should be addressed to M J Young: [email protected] *(M J Young is now at Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia) Abstract MR activation in macrophages is critical for the development of cardiac inflammation Key Words and fibrosis. We previously showed that MR activation modifies macrophage pro- f mineralocorticoid inflammatory signalling, changing the cardiac tissue response to injury via both direct receptor gene transcription and JNK/AP-1 second messenger pathways. In contrast, MR-mediated f macrophage renal electrolyte homeostasis is critically determined by DNA-binding-dependent f JNK processes. Hence, ascertaining the relative contribution of MR actions via DNA binding f cardiac fibrosis or alternative pathways on macrophage behaviour and cardiac inflammation may f non-genomic provide therapeutic opportunities which separate the cardioprotective effects of MR f nuclear receptor antagonists from their undesirable renal potassium-conserving effects.
    [Show full text]
  • Neurod Family Transcription Factors Regulate Corpus Callosum Formation and Cell Differentiation During Cerebral Cortical Development
    Aus dem Institut für Cell und Neurobiologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin DISSERTATION NeuroD Family Transcription Factors Regulate Corpus Callosum Formation and Cell Differentiation during Cerebral Cortical Development zur Erlangung des akademischen Grades Doctor of Philosophy (PhD) Im Rahmen des International Graduate Program Medical Neurosciences vorgelegt der Medizinischen Fakultät Charité – Universitätsmedizin Berlin von Kuo Yan aus: Jinan, China Datum der Promotion: 5. Juni 2016 1 Table of Contents Abstract .................................................................................................................... 5 Zusammenfassung .................................................................................................. 7 1. Introduction ......................................................................................................... 9 1.1 Cerebral cortex development ………………………………………...................... 9 1.1.1 Layering and wiring of the neocortex ........................................................... 9 1.1.2 Formation of the corpus callosum ................................................................ 12 1.2 Basic helix-loop-helix transcription factors ........................................................ 13 1.2.1 NeuroD family transcription factors .............................................................. 14 1.2.2 NeuroD2/6 double deficient mice as a model for axogenesis study ............ 15 1.3 Ephrin-Eph signaling ........................................................................................
    [Show full text]
  • Neurod Is Required for Differentiation of the Granule Cells in the Cerebellum and Hippocampus
    Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION rons (Lee et al. 1995). neuroD is also expressed in pan- NeuroD is required creatic ␤ cells, and NeuroD-null mice become severely for differentiation of the diabetic and die shortly after birth due to defects in ␤ cell granule cells in the cerebellum differentiation (Naya et al. 1995, 1997). To investigate whether NeuroD is involved in postnatal brain develop- and hippocampus ment, we have rescued NeuroD-null mice from neonatal lethality by re-expressing NeuroD in the pancreas using Takaki Miyata, Tomoko Maeda, the transgenic constructs shown in Figure 1. The trans- 1 and Jacqueline E. Lee gene (Tg) contains a short rat insulin promoter (RIP-1; Department of Molecular, Cellular, and Developmental Hanahan 1985) and a coding region that encodes the Biology, University of Colorado at Boulder, mouse NeuroD protein with its amino terminus fused to Boulder, Colorado 80309-0347 USA a Myc tag. We report here that NeuroD-null mice carry- ing the transgene, which we refer to as ND−/−Tg, survive NeuroD, a bHLH transcription factor, is implicated in to adulthood. However, these mice display severe neu- differentiation of neurons and pancreatic ␤ cells. Neu- rological symptoms and morphological defects in the roD-null mice die shortly after birth due to severe neo- brain, indicating that NeuroD has a critical role in post- natal diabetes. To examine if there is postnatal neuronal natal brain development. phenotype in these mice, we rescued them from neona- tal lethality by introducing a transgene encoding the Results mouse neuroD gene under the insulin promoter.
    [Show full text]
  • Generation of Gene-Corrected Functional Osteoclasts From
    Xian et al. Stem Cell Research & Therapy (2020) 11:179 https://doi.org/10.1186/s13287-020-01701-y RESEARCH Open Access Generation of gene-corrected functional osteoclasts from osteopetrotic induced pluripotent stem cells Xiaojie Xian1†, Roksana Moraghebi1†, Henrik Löfvall1,2, Anders Fasth3, Kim Henriksen2, Johan Richter1, Niels-Bjarne Woods1 and Ilana Moscatelli1* Abstract Background: Infantile malignant osteopetrosis (IMO) is an autosomal recessive disorder characterized by non- functional osteoclasts and a fatal outcome early in childhood. About 50% of patients have mutations in the TCIRG1 gene. Methods: IMO iPSCs were generated from a patient carrying a homozygous c.11279G>A (IVS18+1) mutation in TCIRG1 and transduced with a lentiviral vector expressing human TCIRG1. Embryoid bodies were generated and differentiated into monocytes. Non-adherent cells were harvested and further differentiated into osteoclasts on bovine bone slices. Results: Release of the bone resorption biomarker CTX-I into the media of gene-corrected osteoclasts was 5-fold higher than that of the uncorrected osteoclasts and 35% of that of control osteoclasts. Bone resorption potential was confirmed by the presence of pits on the bones cultured with gene-corrected osteoclasts, absent in the uncorrected IMO osteoclasts. Conclusions: The disease phenotype was partially corrected in vitro, providing a valuable resource for therapy development for this form of severe osteopetrosis. Keywords: Infantile malignant osteopetrosis, iPSC generation, Gene transfer, Osteoclast differentiation Background [3, 4]. Furthermore, compression of the cranial nerves Infantile malignant osteopetrosis (IMO) is the most se- leads to impairment of neurologic functions with blind- vere form of the genetically heterogeneous group of dis- ness and sometimes also deafness [3, 4].
    [Show full text]