Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia
Journal
Pediatric Research
Journal Volume
63
Journal Issue
6
Pages
667-673
Date Issued
2008
Author(s)
Liu Y.-J.
Chen H.-L.
Wu S.-H.
Tseng H.-C.
Abstract
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 (OSTα/β) 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. Copyright ? 2008 International Pediatric Research Foundation, Inc.
Other Subjects
cell nucleus receptor; constitutive androstane receptor; cytochrome P450; farnesoid X receptor; multidrug resistance protein 2; multidrug resistance protein 3; multidrug resistance protein 4; organic anion transporter; organic anion transporter 1; pregnane X receptor; carrier protein; cell receptor; messenger RNA; adult; article; bile acid blood level; bile duct atresia; bile duct obstruction; bilirubin blood level; cell transport; child; cholestasis; clinical article; controlled study; effusion; female; human; human cell; human tissue; infant; liver cell; liver sinusoid; male; preschool child; priority journal; protein expression; upregulation; adaptation; bile; bile duct atresia; chemistry; comparative study; disease course; fluorescence microscopy; genetics; intrahepatic cholestasis; liver; liver transplantation; metabolism; newborn; pathology; pathophysiology; prognosis; Adaptation, Physiological; Bile; Biliary Atresia; Cholestasis, Intrahepatic; Disease Progression; Female; Hepatocytes; Humans; Infant; Infant, Newborn; Liver; Liver Transplantation; Male; Membrane Transport Proteins; Microscopy, Fluorescence; Prognosis; Receptors, Cytoplasmic and Nuclear; RNA, Messenger
Type
journal article