Chen Huey-Ling, Liu Yu-Jung, Chen Hui-Ling, Wu Shang-Hsin, Ni Yen-Hsuan, Ho Ming-Chih, Lai Hong-Shiee, Hsu Wen-Ming, Hsu Hong-Yuan, Tseng Hui-Chih, Jeng Yung-Ming, Chang Mei-Hwei
Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, 10002 Taiwan.
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.
为研究肝脏如何适应慢性阻塞性胆汁淤积，对早期和晚期胆汁淤积婴儿的肝脏样本进行分析，以检测肝细胞转运体和核受体水平的变化。在早期胆汁淤积时，大多数胆小管转运体和窦状隙摄取转运体下调，包括胆盐输出泵（BSEP，ABCB11）、多药耐药蛋白3（MDR3，ABCB4）、多药耐药相关蛋白2（MRP2，ABCC2）、钠依赖性牛磺胆酸盐共转运多肽（NTCP，SLC10A1）、有机阴离子转运体（OATP，SLCO1A2）以及核受体法尼醇X受体（FXR，NR1H4）。在晚期胆汁淤积时，FXR - BSEP水平恢复正常，MDR3和MDR1（ABCB1）上调，MRP - 2下调。此外，替代性窦状隙外流转运体有机溶质转运体α/β（OSTα/β）和MRP4上调，孕烷X受体（PXR，NR1I2）水平降低。细胞色素酶P450 7A1在早期和晚期胆汁淤积时均显著下调。对18例患者的长期预后分析显示，预后不良组的PXR和组成型雄甾烷受体（CAR，NR1I3）水平较低。总之，在长期胆汁淤积时，肝细胞胆汁外排通过窦状隙和胆小管转运体进行，FXR - BSEP水平维持，PXR下调。低PXR和CAR水平与预后不良相关。
