Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Medical Microbiology and Immunology

01.12.2015 | Original Investigation

The anti-obesity drug orlistat reveals anti-viral activity

verfasst von: Elisabeth Ammer, Sandor Nietzsche, Christian Rien, Alexander Kühnl, Theresa Mader, Regine Heller, Andreas Sauerbrei, Andreas Henke

Erschienen in: Medical Microbiology and Immunology | Ausgabe 6/2015

Einloggen, um Zugang zu erhalten

Abstract

The administration of drugs to inhibit metabolic pathways not only reduces the risk of obesity-induced diseases in humans but may also hamper the replication of different viral pathogens. In order to investigate the value of the US Food and Drug Administration-approved anti-obesity drug orlistat in view of its anti-viral activity against different human-pathogenic viruses, several anti-viral studies, electron microscopy analyses as well as fatty acid uptake experiments were performed. The results indicate that administrations of non-cytotoxic concentrations of orlistat reduced the replication of coxsackievirus B3 (CVB3) in different cell types significantly. Moreover, orlistat revealed cell protective effects and modified the formation of multi-layered structures in CVB3-infected cells, which are necessary for viral replication. Lowering fatty acid uptake from the extracellular environment by phloretin administrations had only marginal impact on CVB3 replication. Finally, orlistat reduced also the replication of varicella-zoster virus moderately but had no significant influence on the replication of influenza A viruses. The data support further experiments into the value of orlistat as an inhibitor of the fatty acid synthase to develop new anti-viral compounds, which are based on the modulation of cellular metabolic pathways.
Literatur
1.
Kremers S, Reubsaet A, Martens M, Gerards S, Jonkers R, Candel M, de Weerdt I, de Vries N (2010) Systematic prevention of overweight and obesity in adults: a qualitative and quantitative literature analysis. Obes Rev 11(5):371–379CrossRefPubMed
2.
Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ (2014) 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 129(25):102–138CrossRef
3.
Browne CD, Hindmarsh EJ, Smith JW (2006) Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J 20(12):2027–2035CrossRefPubMed
4.
Charakida M, Tousoulis D, Finer N (2013) Drug treatment of obesity in the cardiovascular patient. Curr Opin Cardiol 28(5):584–591CrossRefPubMed
5.
Siebenhofer A, Jeitler K, Horvath K, Berghold A, Siering U, Semlitsch T (2013) Long-term effects of weight-reducing drugs in hypertensive patients. Cochrane Database Syst Rev 3:CD007654PubMed
6.
7.
Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW (2004) Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res 64(6):2070–2075CrossRefPubMed
8.
Guinea R, Carrasco L (1990) Phospholipid biosynthesis and poliovirus genome replication, two coupled phenomena. EMBO J 9(6):2011–2016PubMedCentralPubMed
9.
Kemball CC, Alirezaei M, Flynn CT, Wood MR, Harkins S, Kiosses WB, Whitton JL (2010) Coxsackievirus infection induces autophagy-like vesicles and megaphagosomes in pancreatic acinar cells in vivo. J Virol 84(23):12110–12124PubMedCentralCrossRefPubMed
10.
Van Kuppeveld FJ, Hoenderop JG, Smeets RL, Willems PH, Dijkman HB, Galama JM, Melchers WJ (1997) Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release. EMBO J 16(12):3519–3532PubMedCentralCrossRefPubMed
11.
Limpens RW, van der Schaar HM, Kumar D, Koster AJ, Snijder EJ, van Kuppeveld FJ, Barcena M (2011) The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. MBio 2(5):e00166-11PubMedCentralCrossRefPubMed
12.
Netherton CL, Wileman T (2011) Virus factories, double membrane vesicles and viroplasm generated in animal cells. Curr Opin Virol 1(5):381–387CrossRefPubMed
13.
Robinson SM, Tsueng G, Sin J, Mangale V, Rahawi S, McIntyre LL, Williams W, Kha N, Cruz C, Hancock BM, Nguyen DP, Sayen MR, Hilton BJ, Doran KS, Segall AM, Wolkowicz R, Cornell CT, Whitton JL, Gottlieb RA, Feuer R (2014) Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog 10(4):e1004045PubMedCentralCrossRefPubMed
14.
15.
Belov GA, Altan-Bonnet N, Kovtunovych G, Jackson CL, Lippincott-Schwartz J, Ehrenfeld E (2007) Hijacking components of the cellular secretory pathway for replication of poliovirus RNA. J Virol 81(2):558–567PubMedCentralCrossRefPubMed
16.
Nchoutmboube JA, Viktorova EG, Scott AJ, Ford LA, Pei Z, Watkins PA, Ernst RK, Belov GA (2013) Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles. PLoS Pathog 9(6):e1003401PubMedCentralCrossRefPubMed
17.
Tabor-Godwin JM, Tsueng G, Sayen MR, Gottlieb RA, Feuer R (2012) The role of autophagy during coxsackievirus infection of neural progenitor and stem cells. Autophagy 8(6):938–953PubMedCentralCrossRefPubMed
18.
19.
Why HJ, Meany BT, Richardson PJ, Olsen EG, Bowles NE, Cunningham L, Freeke CA, Archard LC (1994) Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation 89(6):2582–2589CrossRefPubMed
20.
Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Prato SD, Elliott JF, Covacci A, Rappuoli R, Roep BO, Marchetti P (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. PNAS 104(12):5115–5120PubMedCentralCrossRefPubMed
21.
Filippi C, von Herrath M (2005) How viral infections affect the autoimmune process leading to type 1 diabetes. Cell Immunol 233(2):125–132CrossRefPubMed
22.
Feuer R, Mena I, Pagarigan RR, Hassett DE, Whitton JL (2004) Coxsackievirus replication and the cell cycle: a potential regulatory mechanism for viral persistence/latency. Med Microbiol Immunol 193(2–3):83–90CrossRefPubMed
23.
Martin U, Nestler M, Munder T, Zell R, Sigusch HH, Henke A (2004) Characterization of coxsackievirus B3-caused apoptosis under in vitro conditions. Med Microbiol Immunol 193(2–3):133–139PubMed
24.
Rehren F, Ritter B, Dittrich-Breiholz O, Henke A, Lam E, Kati S, Kracht M, Heim A (2013) Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling. Med Microbiol Immunol 202(1):11–23CrossRefPubMed
25.
Huber SA (2005) Increased susceptibility of male BALB/c mice to coxsackievirus B3-induced myocarditis: role for CD1d. Med Microbiol Immunol 194(3):121–127CrossRefPubMed
26.
Rassmann A, Henke A, Jarasch N, Lottspeich F, Saluz HP, Munder T (2007) The human fatty acid synthase: a new therapeutic target for coxsackievirus B3-induced diseases? Antiviral Res 76(2):150–158CrossRefPubMed
27.
Wilsky S, Sobotta K, Wiesener N, Pilas J, Althof N, Munder T, Wutzler P, Henke A (2012) Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication. Arch Virol 157(2):259–269CrossRefPubMed
28.
Nasheri N, Joyce M, Rouleau Y, Yang P, Yao S, Tyrrell DL, Pezacki JP (2013) Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication. Chem Biol 20(4):570–582CrossRefPubMed
29.
Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, Randall G (2010) Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. PNAS 107(40):17345–17350PubMedCentralCrossRefPubMed
30.
Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER (2001) L-ascorbic acid potentiates enodthelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 276(1):40–47CrossRefPubMed
31.
Stahmann N, Woods A, Carling D, Heller R (2006) Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol 26(16):5933–5945PubMedCentralCrossRefPubMed
32.
Knowlton KU, Jeon ES, Berkley N, Wessely R, Huber S (1996) A mutation in the puff region of VP2 attenuates the myocarditic phenotype of an infectious cDNA of the Woodruff variant of coxsackievirus B3. J Virol 70(11):7811–7818PubMedCentralPubMed
33.
Slifka MK, Pagarigan R, Mena I, Feuer R, Whitton JL (2001) Using recombinant coxsackievirus B3 to evaluate the induction and protective efficacy of CD8+ T cells during picornavirus infection. J Virol 75(5):2377–2387PubMedCentralCrossRefPubMed
34.
Sauerbrei A, Zell R, Harder M, Wutzler P (2006) Genotyping of different varicella vaccine strains. J Clin Virol 37(2):109–117CrossRefPubMed
35.
Li Y, Webster-Cyriaque J, Tomlinson CC, Yohe M, Kenney S (2004) Fatty acid synthase expression is induced by the Epstein–Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. J Virol 78(8):4197–4206PubMedCentralCrossRefPubMed
36.
37.
Kühnl A, Rien C, Spengler K, Kryeziu N, Sauerbrei A, Heller R, Henke A (2014) Characterization of coxsackievirus B3 replication in human umbilical vein endothelial cells. Med Microbiol Immunol 203(4):217–229CrossRefPubMed
38.
Moser TS, Schieffer D, Cherry S (2012) AMP-activated kinase restricts Rift Valley fever virus infection by inhibiting fatty acid synthesis. PLoS Pathog 8(4):e1002661PubMedCentralCrossRefPubMed
39.
Guerciolini R (1997) Mode of action of orlistat. Int J Obes Relat Metab Disord 21(3):12–23
40.
Ballinger A, Peikin SR (2002) Orlistat: its current status as an anti-obesity drug. Eur J Pharmacol 440(2–3):109–117CrossRefPubMed
41.
Ameer F, Scandiuzzi L, Hasnain S, Kalbacher H, Zaidi N (2014) De novo lipogenesis in health and disease. Metabolism 63(7):895–902CrossRefPubMed
42.
Rassmann A, Henke A, Zobawa M, Carlsohn M, Saluz HP, Grabley S, Lottspeich F, Munder T (2006) Proteome alterations in human host cells infected with coxsackievirus B3. J Gen Virol 87(9):2631–2638CrossRefPubMed
43.
Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A, Su R, Bapat P, Kwun I, Shen CL (2014) Novel insights of dietary polyphenols and obesity. J Nutr Biochem 25(1):1–18PubMedCentralCrossRefPubMed
44.
Chuang HY, Chang YF, Hwang JJ (2011) Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother 65(4):286–292CrossRefPubMed
45.
Rahman MT, Nakayama K, Ishikawa M, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Iida K, Miyazaki K (2013) Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer. Oncology 84(3):166–173CrossRefPubMed
46.
Kent SJ (2012) Loss of control of HIV viremia associated with the fat malabsorption drug orlistat. AIDS Res Hum Retroviruses 28(9):961–962PubMed
47.
Rust RC, Landmann L, Gosert R, Tang BL, Hong W, Hauri HP, Egger D, Bienz K (2001) Cellular COPII proteins are involved in production of the vesicles that form the poliovirus replication complex. J Virol 75(20):9808–9818PubMedCentralCrossRefPubMed
48.
49.
Belov GA, Ehrenfeld E (2007) Involvement of cellular membrane traffic proteins in poliovirus replication. Cell Cycle 6(1):36–38CrossRefPubMed
50.
Belov GA, Feng Q, Nikovics K, Jackson CL, Ehrenfeld E (2008) A critical role of a cellular membrane traffic protein in poliovirus RNA replication. PLoS Pathog 4(11):e1000216PubMedCentralCrossRefPubMed
51.
Whitton JL, Cornell CT, Feuer R (2005) Host and virus determinants of picornavirus pathogenesis and tropism. Nat Rev Microbiol 3(10):765–776CrossRefPubMed
52.
Richards AL, Jackson WT (2012) Intracellular vesicle acidification promotes maturation of infectious poliovirus particles. PLoS Pathog 8(11):e1003046PubMedCentralCrossRefPubMed
53.
Belov GA, Nair V, Hansen BT, Hoyt FH, Fischer ER, Ehrenfeld E (2012) Complex dynamic development of poliovirus membranous replication complexes. J Virol 86(1):302–312PubMedCentralCrossRefPubMed
54.
55.
Moschen I, Broer A, Galic S, Lang F, Broer S (2012) Significance of short chain fatty acid transport by members of the monocarboxylate transporter family (MCT). Neurochem Res 37(11):2562–2568CrossRefPubMed
56.
Poreba MA, Dong CX, Li SK, Stahl A, Miner JH, Brubaker PL (2012) Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells. Am J Physiol Endocrinol Metab 303(7):899–907CrossRef
57.
Rassmann A, Martin U, Saluz HP, Peter S, Munder T, Henke A (2013) Identification of gene expression profiles in HeLa cells and HepG2 cells infected with Coxsackievirus B3. J Virol Methods 187(1):190–194CrossRefPubMed
58.
Zhang J, Diaz A, Mao L, Ahlquist P, Wang X (2012) Host acyl coenzyme A binding protein regulates replication complex assembly and activity of a positive-strand RNA virus. J Virol 86(9):5110–5121PubMedCentralCrossRefPubMed
59.
Chen JC, Wu ML, Huang KC, Lin WW (2008) HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression. Cardiovasc Res 80(1):138–150CrossRefPubMed
60.
Fedson DS (2013) Treating influenza with statins and other immunomodulatory agents. Antiviral Res 99(3):417–435CrossRefPubMed
61.
Zhu Q, Li N, Han Q, Zhang P, Yang C, Zeng X, Chen Y, Lv Y, Liu X, Liu Z (2013) Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: a systematic review and meta-analysis. Antiviral Res 98(3):373–379CrossRefPubMed
62.
Adhikari RP, Novick RP (2005) Subinhibitory cerulenin inhibits staphylococcal exoprotein production by blocking transcription rather than by blocking secretion. Microbiology 151(9):3059–3069CrossRefPubMed
63.
Yao J, Abdelrahman YM, Robertson RM, Cox JV, Belland RJ, White SW, Rock CO (2014) Type II fatty acid synthesis is essential for the replication of chlamydia trachomatis. J Biol Chem 289(32):22365–22376PubMedCentralCrossRefPubMed
64.
Chayakulkeeree M, Rude TH, Toffaletti DL, Perfect JR (2007) Fatty acid synthesis is essential for survival of Cryptococcus neoformans and a potential fungicidal target. Antimicrob Agents Chemother 51(10):3537–3545PubMedCentralCrossRefPubMed
Metadaten
Titel
The anti-obesity drug orlistat reveals anti-viral activity
verfasst von
Elisabeth Ammer
Sandor Nietzsche
Christian Rien
Alexander Kühnl
Theresa Mader
Regine Heller
Andreas Sauerbrei
Andreas Henke
Publikationsdatum
01.12.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Medical Microbiology and Immunology / Ausgabe 6/2015
Print ISSN: 0300-8584
Elektronische ISSN: 1432-1831
DOI
https://doi.org/10.1007/s00430-015-0391-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise