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Int J Clin Exp Pathol 2013;6(1):80-90

Original Article
Hepatoprotection in bile duct ligated mice mediated by darbepoetin-α is not caused by
changes in hepatobiliary transporter expression

Christian Eipel, Elena Menschikow, Michael Sigal, Angela Kuhla, Kerstin Abshagen, Brigitte Vollmar

Institute for Experimental Surgery, University of Rostock, Schillingallee 69 a, 18055 Rostock, Germany

Received October 24, 2012; Accepted November 10, 2012; Epub November 20, 2012; Published January 1, 2013

Abstract: Aims: 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. Main 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. Key findings: 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. Significance: 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. (IJCP1210015).

Keywords: Bile duct ligation, cholestasis, erythropoietin, slc10a1, abcc4

Address all correspondence to:
Dr. Christian Eipel
University of Rostock, Institute for Experimental Surgery
Schillingallee 69a, D-18057 Rostock, Germany.
Fax: +49 381 494 25 02
E-mail: christian.eipel@uni-rostock.de