Activation of Constitutive Androstane Receptor (CAR) in mice results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver
Open accessAbstract
Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.
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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 [12]
The Introduction (page unavailable) describes CAR’s role in inducing genes involved in drug and xenobiotic detoxification. The Results section on liver weight and bile flow reports increased liver weight in mice after CAR activation, and the Discussion describes changes in bile-acid metabolism. Our copy does not establish a role for CAR in liver proliferation, so that part of the attributed claim is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBA composition differs by sex.
“Consistent with previous reports,12,30 we observed sex differences in BA composition (Figure 4C–F).”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [12]
CAR activation and CAR deficiency did not alter ileal Fxr and Fgf15 transcript expression.
“Moreover, CAR activation12 and deficiency30 did not alter this axis, indicating that the regulation of ileal Fxr and Fgf15 transcript expression is CAR-independent.”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [12]
CAR 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 [12]
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Okuda, H., Sorrentino, D. R., Alpini, G. D., et al. (1988) · Experimental Biology and Medicine · doi:10.3181/00379727-187-42655 · Cited by 7 · see citing works
Effects of Bile Salts on the Plasma Membranes of Isolated Hepatocytes
BILLINGTON, D., EVANS, C. E., GODFREY, P. P., & COLEMAN, R. (1979) · Biochemical Society Transactions · doi:10.1042/bst0070947
Flagged first, then by citations
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Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review
Abdelmonem, B. H., Abdelaal, N. M., Anwer, E. K. E., Rashwan, A. A., Hussein, M. A., Ahmed, Y. F., Khashana, R., Hanna, M. M., & Abdelnaser, A. (2024) · Biomedicines · doi:10.3390/biomedicines12071467 · Cited by 175 · see citing works
“However, CAR receptors do not bind to bile acids directly as they bind to bile acid toxic metabolites in the case of cholestasis [133].”
BackgroundSchlezinger, J. J., Puckett, H. M., Oliver, J., Nielsen, G. H., Heiger‐Bernays, W., & Webster, T. F. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115204 · Cited by 119 · see citing works
The xenobiotic receptors PXR and CAR in liver physiology, an update
Cai, X., Young, G. M., & Xie, W. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166101 · Cited by 84 · see citing works
PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice
Li, C. Y., Dempsey, J. L., Wang, D., Lee, S., Weigel, K. M., Fei, Q., Bhatt, D. K., Prasad, B., Raftery, D., Gu, H., et al. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.081547 · Cited by 78 · see citing works
“In laboratory animals, activation of the xenobiotic sensor CAR by phenobarbital decreased BAs in mouse liver but increased fecal excretion of muricholic acids (Sberna et al., 2011; Lickteig et al., 2016).”
BackgroundMolecular Regulation of Bile Acid Homeostasis
Choudhuri, S., & Klaassen, C. D. (2021) · Drug Metabolism and Disposition · doi:10.1124/dmd.121.000643 · Cited by 72 · see citing works
Self-citationImidacloprid disturbed the gut barrier function and interfered with bile acids metabolism in mice
Yang, G., Yuan, X., Jin, C., Wang, D., Wang, Y., Miao, W., & Jin, Y. (2020) · Environmental Pollution · doi:10.1016/j.envpol.2020.115290 · Cited by 71 · see citing works
Dempsey, J. L., Wang, D., Siginir, G., Fei, Q., Raftery, D., Gu, H., & Cui, J. Y. (2018) · Toxicological Sciences · doi:10.1093/toxsci/kfy271 · Cited by 53 · see citing works
Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation
Cheng, S., Zou, M., Liu, Q., Kuang, J., Shen, J., Pu, S., Chen, L., Li, H., Wu, T., Li, R., et al. (2017) · American Journal Of Pathology · doi:10.1016/j.ajpath.2016.12.013 · Cited by 40 · see citing works
“This finding is consistent with the notion that Mrp4 was a target gene of CAR.23 With a CD, TCPOBOP significantly up-regulated the expression of Oatp2 and sodium (Naþ)-taurocholate cotransport protein, two transporters for hepatic uptake of BAs.”
BackgroundInfluentialNi, Y., Hu, Y., Lou, X., Rong, N., Liu, F., Yang, C., Zheng, A., Yang, S. T., Bao, J., & Fu, Z. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c02729 · Cited by 36 · see citing works
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. (2019) · Hepatology Communications · doi:10.1002/hep4.1274 · Cited by 27 · see citing works
“CAR activation induces both canalicular and basolateral BA transporters, including Abcb11/BSEP, Abcc2/MRP2, and Abcc3/MRP3, to enhance BA excretion.(21,25) Both DKO and BKO mice showed a tendency toward increased fecal BA excretion on TC treatment, whereas urinary BAs were increased in DKO mice (Fig.”
BackgroundBile acids and their receptors in hepatic immunity
Fiorucci, S., Marchianò, S., Distrutti, E., & Biagioli, M. (2025) · Liver Research · doi:10.1016/j.livres.2025.01.005 · Cited by 28 · see citing works
“113 Furthermore, CAR modulates immune responses in DILI by reducing immune cell recruitment to sites of liver injury and suppressing the release of DAMPs, which can trigger further immune activation.”
Li, C. Y., Cheng, S. L., Bammler, T. K., & Cui, J. Y. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw127 · Cited by 23 · see citing works
Bile acids and bile acid activated receptors in the treatment of Covid-19
Fiorucci, S., Urbani, G., Biagioli, M., Sepe, V., Distrutti, E., & Zampella, A. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115983 · Cited by 19 · see citing works
Csanaky, I. L., Lickteig, A. J., & Klaassen, C. D. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.02.005 · Cited by 18 · see citing works
“…transcription quantitative polymerase chain reaction (RT-qPCR) was applied, namely Abca1, Abcg5, Abcg8, Atp8b1, Bcrp, ß-klotho, Ent1, Ibabp, Mate1, Mdr1, Mrp1, Mrp4, Mrp6, Oatp1a4, Oatp2b1, Oat2, Oct1, Ostα, and Ostß as described recently in detail (Lickteig et al., 2016; Renaud et al., 2016).”
BackgroundResultInfluentialSelf-citationConstitutive androstane receptor mediates PCB-induced disruption of retinoid homeostasis
Shmarakov, I. O., Lee, Y. J., Jiang, H., & Blaner, W. S. (2019) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2019.114731 · Cited by 17 · see citing works
Загоскин, П. П., & Erlykina, E. I. (2020) · Современные технологии в медицине · doi:10.17691/stm2020.12.5.13 · Cited by 15 · see citing works
“Thus, the experiments on mice demonstrated that artificial activation of CAR protects the liver from damage caused by bile acids [105].”
BackgroundEffects of ablation and activation of Nrf2 on bile acid homeostasis in male mice
Zhang, Y., Lickteig, A. J., Liu, J., Csanaky, I. L., & Klaassen, C. D. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115170 · Cited by 12 · see citing works
“The mRNAs were quantified using multiplex suspension arrays (Panomics/Affymetrix, Fremont, CA), as described previously (Lickteig et al., 2016; Zhang et al., 2017).”
MethodSelf-citationLickteig, A. J., Zhang, Y., Klaassen, C. D., & Csanaky, I. L. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz143 · Cited by 7 · see citing works
“The major BA TCA also tended to be decreased ( 29”
BackgroundMethodInfluentialSelf-citationActivation of Nrf2 decreases bile acid concentrations in livers of female mice
Liu, J., Lickteig, A. J., Zhang, Y., et al. (2021) · Xenobiotica · doi:10.1080/00498254.2021.1880033 · Cited by 6 · see citing works
Self-citationCsanaky, I. L., Lickteig, A. J., Zhang, Y., & Klaassen, C. D. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115136 · Cited by 5 · see citing works
“In addition to the bead array, for some mRNAs, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used, namely for Abca1, Abcg5, Abcg8, Atp8b1, Bcrp, ß-klotho, Ent1, Ibabp, Mate1, Mdr1, Mrp1, Mrp4, Mrp6, Oatp1a4, Oatp2b1, Oat2, Oct1, Ostα, and Ostß as described in detail (Lickteig et al., 2016;…”
MethodSelf-citationSharma, B., Sethi, B., Raj, S., et al. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2198010 · Cited by 2 · see citing works
“CAR (Constitutive androstane receptor) is a key regulator of cholesterol (Masuyama et al., 2016) as well as the bilirubin clearance pathway (Yin et al., 1991; Huang et al., 2003; Lickteig et al., 2016; Kim et al., 2019).”
BackgroundAMPK activation prevents hepatocellular carcinoma development through inhibition of HNF4α activityPreprint
Sun, Z., Linares, B., Urdiales, C., Al-sarmi, F., Putluri, N., & Nostrand, J. L. V. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.16.652569 · Cited by 2 · see citing works
Brunner, S. P., Plagge, J., Zimmermann‐Kogadeeva, M., Höring, M., Liebisch, G., Basic, M., Bolsega, S., Janssen, K., Slack, E. M. C., von Gamm, S., et al. (2026) · Nature Microbiology · doi:10.1038/s41564-026-02434-z · Cited by 1 · see citing works
Zhou, W., Chembazhi, U. V., Huang, J., Bangru, S., Dean, A. E., Asokakumar, A., Kalsotra, A., Rudnick, D. A., & Anakk, S. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101858
“Consistent with previous reports, 12,30 we observed sex differences in BA composition (Figure 4 C– lower hydrophilic muricholic acid (MCA) at 0 hours, which was increased at 36 and 72 hours post-PHx (Figure 4 C ).”
Sun, Z., Linarés, B., Urdiales, C., Al-sarmi, F., Sang, B., Putluri, N., & Nostrand, J. L. V. (2026) · Science Advances · doi:10.1126/sciadv.aea8017
“5D) ( 84 ).”
Bajnokova, M., Laštůvková, H., Ambrož, M., Hroch, M., Štefela, A., Hricová, J., Smutná, L., Schreiberová, J., Kučera, O., Manna, D. F., et al. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.08.027
- Authors
- Lickteig, A. J., Csanaky, I. L., Pratt-Hyatt, M., & Klaassen, C. D.
- Affiliations
- University of Kansas Medical Center (US)
- Children's Mercy Hospital (US)
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-16
- Volume
- 151
- Issue
- 2
- Pages
- 403-418
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC4880140
- OpenAlex
- W2308301435
- Semantic Scholar
- 9b4e46d04c6727c0ab68eaa8fd81113d977ad797
- Cited by
- 26
- References
- 90
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Toxicological Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK092069)
- National Institute of Environmental Health Sciences (R01ES025708, R01ES009649)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- constitutive androstane receptor, bile acids, biliary excretion, bile flow, taurocholate, CYP8B1, CYP7A1, FGF15, bile acid synthesis, bile acid transport, sex differences, TCPOBOP, liver injury prevention, ileum
- MeSH terms
- Constitutive Androstane Receptor, Animals, Bile, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Female, Fibroblast Growth Factors, Ileum, Liver, Male, Mice, Inbred C57BL, Pyridines, RNA, Messenger, Steroid 12-alpha-Hydroxylase, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Membrane Transport Proteins, Hepatobiliary Elimination
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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