Effects of absence of Constitutive Androstane Receptor (CAR) on bile acid homeostasis in male and female mice
Open accessAbstract
Accumulation of bile acids (BAs) in hepatocytes has a role in liver disease and also in drug-induced liver injury. The constitutive androstane receptor (CAR) has been shown to protect against BA-induced liver injury. The polymorphism of CAR has recently been shown to modify the pharmacokinetics and pharmacodynamics of various drugs. Thus, it was hypothesized that polymorphism of CAR may also influence BA homeostasis. Using CAR-null and WT mice, this study modeled the potential consequences of CAR polymorphism on BA homeostasis. Our previous study showed that chemical activation of CAR decreases the total BA concentrations in livers of mice. Surprisingly the absence of CAR also decreased the BA concentrations in livers of mice, but to a lesser extent than in CAR-activated mice. Neither CAR activation nor elimination of CAR altered the biliary excretion of total BAs, but CAR activation increased the proportion of 6-OH BAs (TMCA), whereas the lack of CAR increased the excretion of taurocholic acid, TCDCA, and TDCA. Serum BA concentrations did not parallel the decrease in BA concentrations in the liver in either the mice after CAR activation or mice lacking CAR. Gene expression of BA synthesis, transporter and regulator genes were mainly similar in livers of CAR-null and WT mice. In summary, CAR activation decreases primarily the 12-OH BA concentrations in liver, whereas lack of CAR decreases the concentrations of 6-OH BAs in liver. In bile, CAR activation increases the biliary excretion of 6-OH BAs, whereas absence of CAR increases the biliary excretion of 12-OH BAs and TCDCA.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Expression of genes involved in cell proliferation and BA homeostasis reveals sex differences.
“In addition, the expression of genes involved in cell proliferation and BA homeostasis also revealed sex differences.30”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [30]
The Results and Discussion report sex-specific expression of genes involved in bile acid synthesis and transport in CAR-null mice. The passages do not report sex differences in the expression of cell-proliferation genes, so that part of the sentence is unsupported. Page numbers were not available in our copy. (LLM, conf=0.86)
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 [30]
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 [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bile Acids: Natural Ligands for an Orphan Nuclear Receptor
Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., Stimmel, J. B., Willson, T. M., Zavacki, A. M., Moore, D. D., et al. (1999) · Science · doi:10.1126/science.284.5418.1365 · Cited by 2,274 · see citing works
The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
Russell, D. W. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161712 · Cited by 2,069 · see citing works
A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00051-4 · Cited by 1,940 · see citing works
Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis
Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C. L., McDonald, J. G., Luo, G., Jones, S. A., Goodwin, B., Richardson, J. A., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.001 · Cited by 1,865 · see citing works
Molecular Basis for Feedback Regulation of Bile Acid Synthesis by Nuclear Receptors
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., & Mangelsdorf, D. J. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00050-2 · Cited by 1,487 · see citing works
Bile-acid-induced cell injury and protection
Perez, M. J., & Briz, O. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.1677 · Cited by 717 · see citing works
Molecular Pathogenesis of Cholestasis
Trauner, M. A., Meier, P. J., & Boyer, J. L. (1998) · New England Journal of Medicine · doi:10.1056/nejm199810223391707 · Cited by 701 · see citing works
Holt, J. A., Luo, G., Billin, A. N., Bisi, J., McNeill, Y. Y., Kozarsky, K., Donahee, M. H., Wang, D. Y., Mansfield, T. A., Kliewer, S. A., et al. (2003) · Genes & Development · doi:10.1101/gad.1083503 · Cited by 698 · see citing works
Molecular Pathogenesis of Cholestasis
Trauner, M. A., & Jansen, P. L. M. (2004) · Springer eBooks · doi:10.1007/978-1-4419-9034-1 · Cited by 612 · see citing works
Bile acids: Chemistry, physiology, and pathophysiology
Monte, M. J., Marı́n, J. J. G., Antelo, Á., & Tato, J. V. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.804 · Cited by 569 · see citing works
Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions.
Heuman, D. M. (1989) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38331-0 · Cited by 555 · see citing works
Ueda, A., Hamadeh, H. K., Webb, H. K., Yamamoto, Y., Sueyoshi, T., Afshari, C. A., Lehmann, J. M., & Negishi, M. (2002) · Molecular Pharmacology · doi:10.1124/mol.61.1.1 · Cited by 465 · see citing works
Kong, B., Wang, L., Chiang, J. Y. L., Zhang, Y., Klaassen, C. D., & Guo, G. L. (2012) · Hepatology · doi:10.1002/hep.25740 · Cited by 456 · see citing works
Self-citationThe Turnover of Cholic Acid in Man.* Bile Acids and Steroids 51.
Lindstedt, S. (1957) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1957.tb01473.x · Cited by 431 · see citing works
Song, K., Li, T., Owsley, E., Strom, S. C., & Chiang, J. Y. L. (2008) · Hepatology · doi:10.1002/hep.22627 · Cited by 414 · see citing works
Dawson, P. A., Hubbert, M. L., Haywood, J., Craddock, A. L., Zerangue, N., Christian, W. V., & Ballatori, N. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412752200 · Cited by 381 · see citing works
Hofmann, A. F., & Hagey, L. R. (2014) · Journal of Lipid Research · doi:10.1194/jlr.r049437 · Cited by 360 · see citing works
FGF-19, A NOVEL FIBROBLAST GROWTH FACTOR WITH UNIQUE SPECIFICITY FOR FGFR4
Xie, M.-H., Holcomb, I. N., Deuel, B., Dowd, P., Huang, A. J. Y., Vagts, A. J., Foster, J., Liang, J., Brush, J., Gu, Q., et al. (1999) · Cytokine · doi:10.1006/cyto.1999.0485 · Cited by 301 · see citing works
Bile Acids, Liver Injury, and Liver Disease
Palmer, R. H. (1972) · Archives of Internal Medicine · doi:10.1001/archinte.1972.03650040130012 · Cited by 281 · see citing works
Alnouti, Y., Csanaky, I. L., & Klaassen, C. D. (2008) · Journal of Chromatography B · doi:10.1016/j.jchromb.2008.08.018 · Cited by 259 · see citing works
Self-citationAleksunes, L. M., & Klaassen, C. D. (2012) · Drug Metabolism and Disposition · doi:10.1124/dmd.112.045112 · Cited by 259 · see citing works
Self-citationZhang, J., Huang, W., Qatanani, M., Evans, R. M., & Moore, D. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409041200 · Cited by 246 · see citing works
Assessment of Activity in Chronic Active Liver Disease
Korman, M. G., Hofmann, A. F., & Summerskill, W. H. J. (1974) · New England Journal of Medicine · doi:10.1056/nejm197406202902503 · Cited by 170 · see citing works
CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease
Qatanani, M., & Moore, D. D. (2005) · Current Drug Metabolism · doi:10.2174/1389200054633899 · Cited by 167 · see citing works
III. Bile acids and nuclear receptors
Chiang, J. Y. L. (2003) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00417.2002 · Cited by 165 · see citing works
On the Turnover and Excretory Products of Cholic and Chenodeoxycholic Acid in Man
Danielsson, H., Eneroth, P. H. E., Hellström, K., Lindstedt, S., & Sjövall, J. (1963) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)67969-x · Cited by 149 · see citing works
Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice
Zhang, Y., & Klaassen, C. D. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m007641 · Cited by 146 · see citing works
Self-citationEffects of bile salts on the plasma membranes of isolated rat hepatocytes
Billington, D. C., Evans, C., Godfrey, P. P., & COLEMAN, R. (1980) · Biochemical Journal · doi:10.1042/bj1880321 · Cited by 144 · see citing works
Slijepcevic, D., Kaufman, C., Wichers, C. G. K., Gilglioni, E. H., Lempp, F. A., Duijst, S., de Waart, D. R., Elferink, R. P. J. O., Mier, W., Stieger, B., et al. (2015) · Hepatology · doi:10.1002/hep.27694 · Cited by 141 · see citing works
Th2 Skewing by Activation of Nrf2 in CD4+ T Cells
Rockwell, C. E., Zhang, M., Fields, P. E., & Klaassen, C. D. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101712 · Cited by 133 · see citing works
Self-citationCsanaky, I. L., Lü, H., Zhang, Y., Ogura, K., Choudhuri, S., & Klaassen, C. D. (2010) · Hepatology · doi:10.1002/hep.23984 · Cited by 121 · see citing works
Self-citationCombined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice
Uppal, H., Toma, D., Saini, S. P. S., Ren, S., Jones, T. J., & Xie, W. (2005) · Hepatology · doi:10.1002/hep.20512 · Cited by 106 · see citing works
Nuclear Receptors as Drug Targets in Cholestatic Liver Diseases
Halilbasic, E., Baghdasaryan, A., & Trauner, M. A. (2013) · Clinics in Liver Disease · doi:10.1016/j.cld.2012.12.001 · Cited by 98 · see citing works
Cui, J. Y., & Klaassen, C. D. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.04.010 · Cited by 83 · see citing works
Self-citationBhamidimarri, K. R., & Schiff, E. R. (2013) · Clinics in Liver Disease · doi:10.1016/j.cld.2013.07.015 · Cited by 79 · see citing works
Bile acids measured in serum during fasting as a test for liver disease.
Skrede, S., Solberg, H. E., Blomhoff, J. P., & Gjone., E. (1978) · Clinical Chemistry · doi:10.1093/clinchem/24.7.1095 · Cited by 78 · see citing works
Fader, K. A., Nault, R., Zhang, C., Kumagai, K., Harkema, J. R., & Zacharewski, T. R. (2017) · Scientific Reports · doi:10.1038/s41598-017-05656-8 · Cited by 74 · see citing works
Beilke, L. D., Aleksunes, L. M., Holland, R. D., Besselsen, D. G., Beger, R. D., Klaassen, C. D., & Cherrington, N. J. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.023317 · Cited by 73 · see citing works
Self-citationRole of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice
Csanaky, I. L., Aleksunes, L. M., Tanaka, Y., & Klaassen, C. D. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90728.2008 · Cited by 62 · see citing works
Self-citationCui, J. Y., Aleksunes, L. M., Tanaka, Y., Fu, Z. D., Guo, Y., Guo, G. L., Lü, H., Zhong, X., & Klaassen, C. D. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00370.2011 · Cited by 59 · see citing works
Self-citationKinetic analysis of bile acid sulfation by stably expressed human sulfotransferase 2A1 (SULT2A1)
Huang, J., Bathena, S. P., Tong, J., Roth, M. E., Hagenbuch, B., & Alnouti, Y. (2010) · Xenobiotica · doi:10.3109/00498250903514607 · Cited by 55 · see citing works
Swart, M., Whitehorn, H., Ren, Y., Smith, P. J., Ramesar, R., & Dandara, C. (2012) · BMC Medical Genetics · doi:10.1186/1471-2350-13-112 · Cited by 54 · see citing works
Zhang, Y., Zhang, Y., Klaassen, C. D., & Cheng, X. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx237 · Cited by 40 · see citing works
Self-citationMbatchi, L., Brouillet, J., & Evrard, A. (2017) · Pharmacogenomics · doi:10.2217/pgs-2017-0121 · Cited by 35 · see citing works
Chen, D., Guo, F., Shi, J., Zhang, C., Wang, Z., Fan, J., & Peng, Z. (2013) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-13-rg-095 · Cited by 29 · see citing works
Zhang, Y., Lickteig, A. J., Csanaky, I. L., & Klaassen, C. D. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx191 · Cited by 28 · see citing works
Self-citationLickteig, A. J., Csanaky, I. L., Pratt-Hyatt, M., & Klaassen, C. D. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw054 · Cited by 26 · cited 19× · see citing works
“The major BA TCA also tended to be decreased ( 29”
BackgroundMethodInfluentialSelf-citationOrganic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism
Zhang, Y., Csanaky, I. L., Selwyn, F. P., Lehman‐McKeeman, L. D., & Klaassen, C. D. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.05.020 · Cited by 24 · see citing works
Self-citationCsanaky, 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
Self-citationZhang, Y., Lickteig, A. J., Csanaky, I. L., & Klaassen, C. D. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.11.014 · Cited by 14 · see citing works
Self-citationEffect of CAR polymorphism on the pharmacokinetics of artemisinin in healthy Chinese subjects
Zang, M., Zhao, L.-X., Zhu, F., Li, X., Yang, A., & Xing, J. (2014) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2014.10.008 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Molecular 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-citationWang, X., Klaassen, C. D., Chen, X., & Zhang, Y. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100073 · Cited by 17 · see citing works
Self-citationBurkhardt, W., Rausch, T., Klopfleisch, R., Blaut, M., & Braune, A. (2021) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2021.151494 · Cited by 13 · see citing works
Potential role of bile acids in the pathogenesis of necrotizing enterocolitis
Yang, J., Chen, X., Liu, T., & Shi, Y. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122279 · Cited by 11 · 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
Yang, H., Zhang, X., Zhou, D., Zou, J., Xu, L., Chen, M., Zhao, S., Dai, J., Wang, X., Du, X., et al. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118225
- Authors
- Lickteig, A. J., Zhang, Y., Klaassen, C. D., & Csanaky, I. L.
- Affiliations
- University of Kansas Medical Center (US)
- Tianjin University (CN)
- Children's Mercy Hospital (US)
- Corresponding author
- Klaassen, Curtis D
- Csanaky, Iván L
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-06-21
- Volume
- 171
- Issue
- 1
- Pages
- 132-145
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC6735724
- OpenAlex
- W2949841724
- Cited by
- 7
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 1 · 2021: 3
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01 ES009649)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32 DK092069)
- Children's Mercy Startup for ILC
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- constitutive androstane receptor, bile acid homeostasis, biliary excretion, taurocholate, taurochenodeoxycholic acid, taurodeoxycholic acid, drug-induced liver injury, hepatocytes, sex differences
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
