Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis

Endocrinology. 2018 Jun 1;159(6):2435-2446. doi: 10.1210/en.2018-00110.


Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, and Bsep-/- had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)-derived BAs in DKO livers but chenodeoxycholate-derived BAs in Bsep-/- livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport in Bsep-/-. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)-CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis in Fxr:Shp:Car:Pxr quadruple knockouts blocked Cyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO and Bsep-/- was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotes Cyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed in Bsep-/- mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics
  • Animals
  • Cholestasis, Intrahepatic / classification
  • Cholestasis, Intrahepatic / genetics*
  • Cholestasis, Intrahepatic / pathology*
  • Constitutive Androstane Receptor
  • Cytochrome P-450 CYP2B6 / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pregnane X Receptor / genetics
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction / genetics
  • Xenobiotics / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Abcb11 protein, mouse
  • Constitutive Androstane Receptor
  • Nr1i2 protein, mouse
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Xenobiotics
  • nuclear receptor subfamily 0, group B, member 2
  • farnesoid X-activated receptor
  • Cytochrome P-450 CYP2B6

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 1
  • Cholestasis, progressive familial intrahepatic 2