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Cited by 27Drug Transport and Resistance MechanismsCholesterol and Lipid MetabolismPediatric Hepatobiliary Diseases and Treatments

Constitutive Androstane Receptor Differentially Regulates Bile Acid Homeostasis in Mouse Models of Intrahepatic Cholestasis

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Kim, Kang Ho, Choi, Jong Min, Li, Feng, Dong, Bingning, Wooton‐Kee, Clavia Ruth, Arizpe, Armando, Anakk, Sayeepriyadarshini, Jung, Sung Yun +2 more·2019·Hepatology Communications
DOI 10.1002/hep4.1274PMC PMC6312660
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Abstract

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.

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Authors
Kim, K. H., Choi, J. M., Li, F., Dong, B., Wooton‐Kee, C. R., Arizpe, A., Anakk, S., Jung, S. Y., Hartig, S. M., & Moore, D. D.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas at Austin (US)
  • University of Illinois Urbana-Champaign (US)
Corresponding author
Moore, David D.
ORCID
Venue
Hepatology Communications
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-12-04
Volume
3
Issue
1
Pages
147-159
ISSN
2471-254X (ISSN-L)
DOI
10.1002/hep4.1274
PMC
PMC6312660
OpenAlex
W2902260187
Cited by
27
References
7
Citations by year
2026: 5 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2017: 1
FWCI
0.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology Communications (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • American Diabetes Association (18-IBS-105, 1-18-IBS-105, 1-17-IBS-105)
  • Kyungpook National University
  • National Institutes of Health (W81XWH)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK114356, R01DK113080)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
Keywords
constitutive androstane receptor, bile acid homeostasis, intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2, farnesoid X receptor, small heterodimer partner, triple knockout mice, bile salt export pump, ABCB11, TCPOBOP, hepatic cholesterol homeostasis, cholestatic liver injury, fecal bile acid excretion

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