Fibroblast Growth Factor 15–Dependent and Bile Acid–Independent Promotion of Liver Regeneration in Mice
Open accessAbstract
The role of intestine‐derived factors in promoting liver regeneration after partial hepatectomy (PHx) are not entirely known, but bile acids (BAs) and fibroblast growth factor 15 (Fgf15) that is highly expressed in the mouse ileum could promote hepatocyte proliferation. Fgf15 strongly suppresses the synthesis of BAs, and emerging evidence indicates that Fgf15 is important for liver regeneration. The mechanisms by which Fgf15 promotes liver regeneration are unclear, but Fgf15 may do so indirectly by reducing BA levels and/or directly by promoting cell proliferation. However, it remains undetermined whether these two mechanisms are independent or integrated. In this study, we aimed to clarify these relationships by generating Fgf15 Tet‐Off, transgenic mice ( Fgf15 Tg) that had very low BA levels as a result from overexpressed Fgf15‐mediated suppression of BA synthesis. Compared with wild‐type mice, the Fgf15 Tg mice showed increased hepatocyte proliferation even without surgery, and a further induction of the genes in cell‐cycle progression after PHx. Moreover, overexpression of Fgf15 by adeno‐associated virus (AAV)‐ Fgf15 transduction or treatment with the recombinant Fgf15 protein led to increased cell proliferation in vivo . Furthermore, Fgf15 Tg mice exhibited an earlier and greater activation of mitogen‐activated protein kinase, signal transducer and activator of transcription 3, and NF‐κB signaling pathways in the priming stage, and a disruption of the hippo signaling pathway in the termination stage of liver regeneration. Conclusion: Direct in vivo evidence demonstrates that Fgf15 is critical in stimulating the phases of priming and termination of liver regeneration that are critical for cell survival and liver‐size determination, independent of BA levels. (H epatology 2018; 00:000‐000).
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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 [42]
The Introduction states that intestinal FXR induces Fgf15/FGF19, which promotes hepatocyte proliferation and liver regeneration. It also reports that bile-acid depletion by cholestyramine decreased liver regeneration, but it does not say that CHR reduces intestinal FXR–FGF15/19 signaling. No page numbers are available in our copy. (LLM, conf=0.84)
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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
Expression Regulation and Bioactivity of Fibroblast Growth Factor 19/15
白, 玉. (2022) · Pharmacy Information · doi:10.12677/pi.2022.113020
Mechanisms of Liver Regeneration
Kofler, A., Poelsler, L. H., Oberhuber, R., & Primavesi, F. (2026) · Springer eBooks · doi:10.1007/978-3-032-10997-2_1
Zhang, Q., Niu, R.-G., Ding, H., Chen, Z., Shi, Y., Cao, X., & Lan, J. (2026) · Comparative Immunology Reports · doi:10.1016/j.cirep.2026.200273
Rôle des FGFs endocrines et leurs récepteurs au cours de la fibrose pulmonaire idiopathique
Ghanem, M. (2023) · theses.fr (ABES) · doi:10.70675/fd0d64f8zacf4z4856z9b1az66d4df37a332
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- Authors
- Kong, B., Sun, R., Huang, M., Chow, M. D., Zhong, X., Xie, W., Lee, Y., & Guo, G. L.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- China Pharmaceutical University (CN)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- University of Connecticut (US)
- University of Pittsburgh (US)
- Corresponding author
- Guo, Grace L.
- Venue
- Hepatology
- Published
- 2018-10-08
- Volume
- 68
- Issue
- 5
- Pages
- 1961-1976
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6195490
- OpenAlex
- W2801515643
- Cited by
- 52
- References
- 43
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 9 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 11 · 2019: 2 · 2018: 1
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX002741)
- National Institute of General Medical Sciences (R01GM118367, R01GM104037)
- National Institute of Environmental Health Sciences (R21ES029258)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- FGF15, liver regeneration, bile acids, partial hepatectomy, hepatocyte proliferation, MAPK signaling, STAT3 signaling, NF-κB signaling, Hippo signaling pathway, cell cycle progression
- MeSH terms
- Animals, Bile Acids and Salts, Fibroblast Growth Factors, Immunohistochemistry, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Mice, Transgenic, Blotting, Western, Signal Transduction, Hepatocytes, Cell Proliferation, Mice, Real-Time Polymerase Chain Reaction
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