Bile acid (BA) homeostasis is tightly regulated by multiple transcription factors, including farnesoid X receptor (FXR) and small heterodimer partner (SHP). We previously reported that loss of the FXR/SHP axis causes severe intrahepatic cholestasis, similar to human progressive familial intrahepatic cholestasis type 5 (PFIC5). In this study, we found that constitutive androstane receptor (CAR) is endogenously activated in Fxr:Shp double knockout (DKO) mice. To test the hypothesis that CAR activation protects DKO mice from further liver damage, we generated Fxr;Shp;Car triple knockout (TKO) mice. In TKO mice, residual adenosine triphosphate (ATP) binding cassette, subfamily B member 11 (ABCB11; alias bile salt export pump [BSEP]) function and fecal BA excretion are completely impaired, resulting in severe hepatic and biliary damage due to excess BA overload. In addition, we discovered that pharmacologic CAR activation has different effects on intrahepatic cholestasis of different etiologies. In DKO mice, CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP; here on TC) treatment attenuated cholestatic liver injury, as expected. However, in the PFIC2 model Bsep knockout (BKO) mice, TC treatment exhibited opposite effects that reflect increased BA accumulation and liver injury. These contrasting results may be linked to differential regulation of systemic cholesterol homeostasis in DKO and BKO livers. TC treatment selectively up-regulated hepatic cholesterol levels in BKO mice, supporting de novo BA synthesis. Conclusion: CAR activation in DKO mice is generally protective against cholestatic liver injury in these mice, which model PFIC5, but not in the PFIC2 model BKO mice. Our results emphasize the importance of the genetic and physiologic background when implementing targeted therapies to treat intrahepatic cholestasis.
Pubmed ID: 30620001 RIS Download
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Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.
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View all literature mentionsA commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets MRP4 (F-6)
View all literature mentionsThis monoclonal targets Cytokeratin 19 antibody [EPNCIR127B]
View all literature mentionsThis monoclonal targets MRP3 (M3II-21)
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets ABCB11
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets MRP4 (F-6)
View all literature mentionsThis monoclonal targets Cytokeratin 19 antibody [EPNCIR127B]
View all literature mentionsThis monoclonal targets ABCB11
View all literature mentionsThis monoclonal targets MRP3 (M3II-21)
View all literature mentionsThis polyclonal targets IgG
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