Related Experiment Video
Updated: Feb 11, 2026

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
Published on: September 13, 2013
Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic
Kang Ho Kim1, Jong Min Choi1, Feng Li1,2
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Abstract:
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.
More Related Videos
03:45Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
08:08Determination of the Transport Rate of Xenobiotics and Nanomaterials Across the Placenta using the ex vivo Human Placental Perfusion Model
Published on: June 18, 2013
Related Concept Videos
Protein Families
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Gene Families
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Nuclear Localization Signals and Import
Signal Sequences and Sorting Receptors