title: Hepatoprotection in bile duct ligated mice mediated by darbepoetin-α is not caused by changes in hepatobiliary transporter expression.
abstract: OBJECTIVE
  Darbepoetin-α (DPO), a long-acting erythropoietin analog, has been shown to protect the liver against cholestatic injury, to exert an antifibrotic effect, and to increase the survival time in a model of common bile duct ligation. Here we evaluate whether these tissue-protective effects are caused by DPO induced regulation of hepatobiliary transporters.
  
  
  METHODS
  C57BL/6J mice underwent common bile duct ligation and were treated with either DPO or physiological saline. Time dependent (2, 5, 14, 28 days after bile duct ligation) protein expression of different hepatobiliary transporters which have been established to play an important role in hepatocellular (i) bile acid uptake, (ii) bile acid excretion, and (iii) retrograde bile acid efflux were assessed. mRNA and protein expression of Lhx2, an important negative regulator of hepatic stellate cell activation, was determined.
  
  
  RESULTS
  Saline treated cholestatic mice impress with increased mRNA expression of Lhx2 as a defense mechanism, while there is less need for such an upregulation in mice treated with DPO. Whereas Ntcp (slc10a1) protein expression is suppressed as early as 2 days after bile duct ligation to 40% in untreated animals, DPO treated mice exhibit decreased protein level not before day 5. Similarly, the steady decline of Mrp4 (abcc4) protein level during extrahepatic cholestasis in control treated animals does not occur upon DPO application.
  
  
  CONCLUSIONS
  The collected data show that DPO affects expression of hepatobilliary transporters during obstructive cholestasis but do not provide sufficient evidence to demonstrate a direct correlation between this regulation and hepatoprotection by DPO.
authors.affiliation: Institute for Experimental Surgery, University of Rostock Schillingallee 69 a, 18055 Rostock, Germany. christian.eipel@uni-rostock.de
authors.forename: Christian
authors.initials: C
authors.lastname: Eipel
authors.forename: Elena
authors.initials: E
authors.lastname: Menschikow
authors.forename: Michael
authors.initials: M
authors.lastname: Sigal
authors.forename: Angela
authors.initials: A
authors.lastname: Kuhla
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D002779:Cholestasis / Q000378:metabolism*; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D027981:Symporters / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D000068256:Darbepoetin alfa; D004921:Erythropoietin; D060850:LIM-Homeodomain Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D014157:Transcription Factors; C489540:Abcc4 protein, mouse; C489784:Lhx2 protein, mouse; C071908:sodium-bile acid cotransporter