Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in Mice
Open accessAbstract
Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury.
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CAR is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.
“The nuclear receptor, constitutive androstane receptor (CAR; NR1I3), is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.7, 8, 9, 10, 11, 12, 13, 14”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [11]
The Discussion reports that CAR regulates bile acid metabolism, and the introductory passage describes its role in bile acid detoxification and bilirubin clearance (pages unavailable). The paper does not substantively address CAR's role in liver proliferation or hepatomegaly; hepatomegaly appears only in the title of a cited reference. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCAR has a protective function during cholestasis.
“Overall, these findings are consistent with a protective function for CAR during cholestasis.10, 11, 12, 13,54”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [11]
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- Authors
- Beilke, L. D., Aleksunes, L. M., Holland, R. D., Besselsen, D. G., Beger, R. D., Klaassen, C. D., & Cherrington, N. J.
- Affiliations
- University of Arizona (US)
- University of Kansas (US)
- United States Food and Drug Administration (US)
- ORCID
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 37
- Issue
- 5
- Pages
- 1035-1045
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC2683394
- OpenAlex
- W2006709297
- Cited by
- 73
- References
- 37
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 2 · 2013: 10 · 2012: 4
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Food and Drug Administration
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068039, DK-068039)
- National Institute of Environmental Health Sciences (ES 011646, K22ES011646, P30ES006694)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- constitutive androstane receptor, lithocholic acid, bile acid synthesis, hepatoprotection, cholestasis, liver injury, bile acid toxicity, CYP8B1, CYP7B1, CYP27A1, phenobarbital, TCPOBOP, liver necrosis
- MeSH terms
- Constitutive Androstane Receptor, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Chromatography, High Pressure Liquid, DNA, DNA-Binding Proteins, Lithocholic Acid, Liver, Male, Mice, Inbred C57BL, Phenobarbital, Pyridines, RNA, Transcription Factors, Oligonucleotide Probes, Receptors, Cytoplasmic and Nuclear, Spectrometry, Mass, Electrospray Ionization, Mice, Tandem Mass Spectrometry, Chemical and Drug Induced Liver Injury
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