title: Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia.
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 (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.
authors.affiliation: Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, 10002 Taiwan.
authors.forename: Huey-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Liu
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Shang-Hsin
authors.initials: SH
authors.lastname: Wu
authors.forename: Yen-Hsuan
authors.initials: YH
authors.lastname: Ni
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Ho
authors.forename: Hong-Shiee
authors.initials: HS
authors.lastname: Lai
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Hsu
authors.forename: Hui-Chih
authors.initials: HC
authors.lastname: Tseng
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Mei-Hwei
authors.initials: MH
authors.lastname: Chang
mesh_terms: D000222:Adaptation, Physiological; D001646:Bile / Q000378:metabolism; D001656:Biliary Atresia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D002780:Cholestasis, Intrahepatic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D000090702:Constitutive Androstane Receptor; D018450:Disease Progression; D005260:Female; D022781:Hepatocytes / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000089762:Multidrug Resistance-Associated Protein 2; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000235:genetics
chemical_list: C000715087:ABCC2 protein, human; D000090702:Constitutive Androstane Receptor; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; C000716327:NR1I3 protein, human; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear