Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia

Pediatr Res. 2008 Jun;63(6):667-73. doi: 10.1203/PDR.0b013e318170a6b5.


To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Bile / metabolism
  • Biliary Atresia / complications*
  • Biliary Atresia / metabolism
  • Biliary Atresia / physiopathology
  • Biliary Atresia / surgery
  • Cholestasis, Intrahepatic / etiology
  • Cholestasis, Intrahepatic / metabolism*
  • Cholestasis, Intrahepatic / physiopathology
  • Cholestasis, Intrahepatic / surgery
  • Constitutive Androstane Receptor
  • Disease Progression
  • Female
  • Hepatocytes / chemistry*
  • Hepatocytes / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Liver / chemistry*
  • Liver / pathology
  • Liver / physiopathology
  • Liver / surgery
  • Liver Transplantation
  • Male
  • Membrane Transport Proteins / analysis*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Microscopy, Fluorescence
  • Multidrug Resistance-Associated Protein 2
  • Prognosis
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear / analysis*
  • Receptors, Cytoplasmic and Nuclear / genetics


  • ABCC2 protein, human
  • Constitutive Androstane Receptor
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • NR1I3 protein, human
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear