Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose
Open accessAbstract
Bile acids play a critical role in liver injury and regeneration, but their role in acetaminophen (APAP)-induced liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% cholestyramine (CSA)-containing diet for bile acid depletion, or a 0.2% cholic acid (CA)-containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of liver injury and significantly higher liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet-fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced liver injury.
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An unintended consequence of accumulating excess BAs is proliferation.
“An unintended consequence of accumulating excess BAs is proliferation.5,36”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [36]
The ‘Increase in Total Bile Acids and FGF15 mRNA’ section reports that cholic acid supplementation raised bile acid levels, and ‘Mechanisms of Rapid Recovery’ reports greater liver-cell proliferation in supplemented mice after acetaminophen treatment. The claim omits that injury context: the paper says the supplemented mice had no ongoing cell proliferation before acetaminophen treatment, so it does not show that excess bile acids alone cause proliferation. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCHR-fed WT mice show a reduced number of BrdU-positive nuclei compared with chow-fed WT mice, validating a role for the BA spike in liver regeneration.
“It is pertinent to note that CHR-fed WT mice also showed a reduced number of BrdU-positive nuclei compared with chow-fed WT mice (Figure 8E and F), validating a role for the BA spike in liver regeneration, consistent with previous findings.5,36”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [36]
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References 46 · Cited by 79
Research works printed but not linked: 1
- Apte U, Mehendale HM: Hepatic defenses against toxicology: liver regeneration and tissue repair. Edited by McQueen CA, (Ed). Compre- hensive Toxicology. ed 2. Philadelphia, Elsevier, 2009, pp 339e367
- Authors
- Bhushan, B., Borude, P., Edwards, G., Walesky, C., Cleveland, J., Li, F., Ma, X., & Apte, U.
- Affiliations
- University of Kansas Medical Center (US)
- Corresponding author
- Apte, Udayan
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 183
- Issue
- 5
- Pages
- 1518-1526
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3814573
- OpenAlex
- W2063566377
- Cited by
- 79
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 2 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 4
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Liver Foundation
- American Association for the Study of Liver Diseases
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK98414, R01DK098414)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- bile acids, acetaminophen hepatotoxicity, liver injury, liver regeneration, cholestyramine, cholic acid, c-Jun N-terminal kinase, FGF15, cyclin D1, CYP2E1, glutathione depletion
- MeSH terms
- Acetaminophen, Animals, Bile Acids and Salts, Cholestyramine Resin, Feeding Behavior, Fibroblast Growth Factors, Gene Expression Regulation, Intestinal Mucosa, Intestines, Liver, Liver Regeneration, Mice, Inbred C57BL, RNA, Messenger, Mice, Chemical and Drug Induced Liver Injury, Drug Overdose
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