title: Primary biliary acids inhibit hepatitis D virus (HDV) entry into human hepatoma cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP).
abstract: BACKGROUND
  The sodium-taurocholate cotransporting polypeptide (NTCP) is both a key bile acid (BA) transporter mediating uptake of BA into hepatocytes and an essential receptor for hepatitis B virus (HBV) and hepatitis D virus (HDV). In this study we aimed to characterize to what extent and through what mechanism BA affect HDV cell entry.
  
  
  METHODS
  HuH-7 cells stably expressing NTCP (HuH-7/NTCP) and primary human hepatocytes (PHH) were infected with in vitro generated HDV particles. Infectivity in the absence or presence of compounds was assessed using immunofluorescence staining for HDV antigen, standard 50% tissue culture infectious dose (TCID50) assays and quantitative PCR.
  
  
  RESULTS
  Addition of primary conjugated and unconjugated BA resulted in a dose dependent reduction in the number of infected cells while secondary, tertiary and synthetic BA had a lesser effect. This effect was observed both in HuH-7/NTCP and in PHH. Other replication cycle steps such as replication and particle assembly and release were unaffected. Moreover, inhibitory BA competed with a fragment from the large HBV envelope protein for binding to NTCP-expressing cells. Conversely, the sodium/BA-cotransporter function of NTCP seemed not to be required for HDV infection since infection was similar in the presence or absence of a sodium gradient across the plasma membrane. When chenodeoxycolic acid (15 mg per kg body weight) was administered to three chronically HDV infected individuals over a period of up to 16 days there was no change in serum HDV RNA.
  
  
  CONCLUSIONS
  Primary BA inhibit NTCP-mediated HDV entry into hepatocytes suggesting that modulation of the BA pool may affect HDV infection of hepatocytes.
authors: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany; University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07), Sao Paulo, Brazil; Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Isabel
authors: I
authors: Veloso Alves Pereira
authors: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Bettina
authors: B
authors: Buchmann
authors: Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Lisa
authors: L
authors: Sandmann
authors: Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany.
authors: Kathrin
authors: K
authors: Sprinzl
authors: Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Verena
authors: V
authors: Schlaphoff
authors: Institut für Virologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Katinka
authors: K
authors: Döhner
authors: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Florian
authors: F
authors: Vondran
authors: Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany.
authors: Christoph
authors: C
authors: Sarrazin
authors: Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Michael P
authors: MP
authors: Manns
authors: University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07), Sao Paulo, Brazil.
authors: Cláudia
authors: C
authors: Pinto Marques Souza de Oliveira
authors: Institut für Virologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Beate
authors: B
authors: Sodeik
authors: Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Sandra
authors: S
authors: Ciesek
authors: Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany; Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors: Thomas
authors: T
authors: von Hahn
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D060085:Coinfection / Q000821:virology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019694:Hepatitis B, Chronic / Q000821:virology; D019701:Hepatitis D, Chronic / Q000821:virology; D003698:Hepatitis Delta Virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D002635:Chenodeoxycholic Acid; C071908:sodium-bile acid cotransporter; D012964:Sodium
references: N Engl J Med. 1973 Sep 27;289(13):655-9
references: 4580472
references: Cochrane Database Syst Rev. 2003;(2):CD003181
references: 12804455
references: Lancet. 2011 Jul 2;378(9785):73-85
references: 21511329
references: Liver Int. 2014 Feb;34 Suppl 1:139-45
references: 24373091
references: J Hepatol. 2014 Oct;61(4):867-75
references: 24845614
references: Gastroenterology. 2014 Apr;146(4):1070-83
references: 24361467
references: PLoS One. 2011;6(9):e24142
references: 21909416
references: Gut. 1971 Feb;12(2):145-52
references: 5548561
references: Gastroenterology. 1986 Oct;91(4):1007-18
references: 3527851
references: Nat Biotechnol. 2008 Mar;26(3):335-41
references: 18297057
references: J Hepatol. 2014 Apr;60(4):723-31
references: 24295872
references: Hepatology. 2014 May;59(5):1726-37
references: 24375637
references: J Pediatr Surg. 2012 Mar;47(3):501-5
references: 22424345
references: J Virol. 2014 Mar;88(6):3273-84
references: 24390325
references: J Antimicrob Chemother. 2014 Aug;69(8):2123-31
references: 24710028
references: Gastroenterology. 1997 Oct;113(4):1295-305
references: 9322525
references: J Clin Microbiol. 2010 Jun;48(6):2022-9
references: 20351206
references: J Infect Dis. 2014 Mar 1;209(5):658-67
references: 24041792
references: J Virol. 1989 May;63(5):1945-50
references: 2649689
references: N Engl J Med. 2011 Jan 27;364(4):322-31
references: 21268724
references: Curr Infect Dis Rep. 2013 Feb;15(1):31-8
references: 23242761
references: Elife. 2012 Nov 13;1:e00049
references: 23150796
references: Vaccine. 2012 Mar 9;30(12):2212-9
references: 22273662
references: Hepatology. 2014 Jul;60(1):87-97
references: 24585488
references: N Engl J Med. 1972 Jan 6;286(1):1-8
references: 5006919
references: Compr Physiol. 2013 Jul;3(3):1035-78
references: 23897680
references: Cancer Res. 1982 Sep;42(9):3858-63
references: 6286115
references: Methods Mol Biol. 2010;640:463-73
references: 20645068
references: Arch Dermatol. 2007 Jun;143(6):757-62
references: 17576942