Bile Acid Flux Is Necessary for Normal Liver Regeneration
Open accessAbstract
BACKGROUND & AIMS: Many signals governing liver regeneration (LR) following 2/3 partial hepatectomy (PH) are recognized, but the primary signal(s) remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC), which may in turn stimulate LR. METHODS: After standard PH, BA flux was documented and BA signaling (Fgf15) and synthesis (Cyp7a) determined by qPCR. Rat biliary fistula (BF) and Asbt knockout mouse models interrupted the EHC prior to PH, and standard assays for LR employed along with complete RNA sequencing. CCl4 intoxication after BF tested the hypothesis in an alternate injury model. RESULTS: BA rise in systemic blood immediately following PH, confirming that the remnant liver cannot handle the BA returning via portal circulation. When the BA pool is drained prior to PH in the rat BF model, LR is markedly attenuated, a phenomenon reversed with duodenal BA replacement. Hepatocyte proliferation is similarly attenuated after PH in the Asbt knockout mouse as well as after CCl44 intoxication in rats with BF. Complete RNA sequencing in the rat PH model shows that early c-jun and AP-1 gene expression pathways are down regulated in the absence of BA, coincident with attenuated LR. CONCLUSIONS: Absent BA return to the liver after PH or CCl4 injury markedly attenuates LR, though hepatocyte proliferation still occurs, inferring that BA flux and signaling are not the sole signals governing LR. Transcriptional networks involving c-jun and AP-1 are involved in the BA-specific effects on hepatocyte proliferation.
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CHR reduces intestinal FXR-FGF15/19 signaling, which indirectly regulates liver regeneration.
“Because CHR has been shown to reduce farnesoid X receptor (FXR)–fibroblast growth factor 15/19 (FGF15/19) signaling in the intestine that indirectly regulates liver regeneration,5,41,42”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [41]
The Results section reports that interrupting bile-acid circulation by biliary fistula made intestinal Fgf15 undetectable and attenuated liver regeneration; Asbt-knockout mice likewise had nearly undetectable intestinal Fgf15 and diminished regrowth. The Introduction links intestinal FXR and FGF15 to regeneration, but the paper does not show that CHR itself reduces intestinal FXR–FGF15/19 signaling. No page numbers are available in our copy. (LLM, conf=0.84)
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- Authors
- Naugler, W. E.
- Affiliations
- Oregon Health & Science University (US)
- Corresponding author
- Naugler, Willscott E.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-19
- Volume
- 9
- Issue
- 5
- Pages
- e97426
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4026228
- OpenAlex
- W2066567528
- Cited by
- 65
- References
- 40
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 4 · 2015: 9
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK083507, K08DK083507, T32DK007202)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- liver regeneration, partial hepatectomy, enterohepatic circulation, biliary fistula, hepatocyte proliferation, c-Jun, bile acid signaling
- MeSH terms
- Animals, Bile Acids and Salts, Hepatectomy, Liver, Liver Regeneration, Male, Mice, Knockout, Transcription Factor AP-1, Mice, Rats
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.
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