Transcriptomic analysis across liver diseases reveals disease-modulating activation of constitutive androstane receptor in cholestasis
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Abstract
BACKGROUND & AIMS: Liver diseases are caused by many factors, such as genetics, nutrition, and viruses. Therefore, it is important to delineate transcriptomic changes that occur in various liver diseases. METHODS: We performed high-throughput sequencing of mouse livers with diverse types of injuries, including cholestasis, diet-induced steatosis, and partial hepatectomy. Comparative analysis of liver transcriptome from mice and human samples of viral infections (HBV and HCV), alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH), and biliary atresia revealed distinct and overlapping gene profiles associated with liver diseases. We hypothesised that discrete molecular signatures could be utilised to assess therapeutic outcomes. We focused on cholestasis to test and validate the hypothesis using pharmacological approaches. RESULTS: Here, we report significant overlap in the expression of inflammatory and proliferation-related genes across liver diseases. However, cholestatic livers were unique and displayed robust induction of genes involved in drug metabolism. Consistently, we found that constitutive androstane receptor (CAR) activation is crucial for the induction of the drug metabolic gene programme in cholestasis. When challenged, cholestatic mice were protected against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. These protective effects were diminished upon inhibition of CAR activity. Further, drug metabolic genes were also induced in the livers from a subset of biliary atresia patients, but not in HBV and HCV infections, AH, or NASH. We also found a higher expression of CYP2B6, a CAR target, in the livers of biliary atresia patients, underscoring the clinical importance of our findings. CONCLUSIONS: Comparative transcriptome analysis of different liver disorders revealed specific induction of phase I and II metabolic genes in cholestasis. Our results demonstrate that CAR activation may lead to variations in drug metabolism and clinical outcomes in biliary atresia. LAY SUMMARY: Transcriptomic analysis of diverse liver diseases revealed alterations in common and distinct pathways. Specifically, in cholestasis, we found that detoxification genes and their activity are increased. Thus, cholestatic patients may have an unintended consequence on drug metabolism and not only have a beneficial effect against liver toxicity, but also may require adjustments to their therapeutic dosage.
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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 [13]
The Results section on CAR activation reports regulation of detoxification and metabolic genes and upregulation of cell-cycle-associated transcripts, suggesting a role in proliferation. Our copy does not link CAR to hepatomegaly (liver enlargement), so that part of the attributed claim is unsupported. No page numbers are available in the indexed passages. (LLM, conf=0.86)
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- Authors
- Mathur, B., Arif, W., Patton, M. E., Faiyaz, R., Liu, J., Yeh, J., Harpavat, S., Schoonjans, K., Kalsotra, A., Wheatley, A. M., & Anakk, S.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Texas Children's Hospital (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Anakk, Sayeepriyadarshini
- ORCID
- Venue
- JHEP Reports
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 2
- Issue
- 5
- Pages
- 100140
- ISSN
- 2589-5559 (ISSN-L)
- PMC
- PMC7452294
- OpenAlex
- W3039244035
- Cited by
- 14
- References
- 70
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2021: 2 · 2020: 2
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JHEP Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Illinois at Urbana-Champaign
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- cholestasis, constitutive androstane receptor, liver transcriptome, drug metabolism genes, biliary atresia, CYP2B6, acetaminophen hepatotoxicity, nonalcoholic steatohepatitis, alcoholic hepatitis, viral hepatitis, partial hepatectomy
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 ›
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