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.