Nuclear Receptor-Dependent Bile Acid Signaling Is Required for Normal Liver Regeneration
Abstract
Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.
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Acute increases in bile acid levels act as a key pro-regenerative signal for liver regeneration after PHx.
“Notably, acute increases in bile acid (BA) levels act as a key pro-regenerative signal for this process.3, 4, 5”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [5]
Existing reports suggest impaired regeneration in Car knockout mice post-PHx.
“Existing reports suggest impaired regeneration in Car knockout (CarKO) mice post-PHx,5,24 but the temporal dynamics and metabolic functions of CAR during regeneration are yet to be elucidated.”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [5]
CHR-fed WT and CarKO mice exhibit elevated mRNA levels of BA synthesis genes and reduced expression of BA export and detoxification genes compared with chow-fed mice, to compensate for a reduced BA pool.
“To compensate for a reduced BA pool,5,39,40 we observed that CHR-fed WT and CarKO mice exhibited elevated mRNA levels of BA synthesis genes and reduced expression of BA export and detoxification genes compared with chow-fed mice (Figure 10A–C).”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [5]
CHR-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 [5]
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 [5]
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 [5]
Prior reports showed delayed or impaired regeneration in CarKO mice after 70% or ~86% PHx.
“Prior reports showed either delayed or impaired regeneration in CarKO mice following 70% or ∼86% PHx,5,24”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [5]
FXR facilitates liver regeneration via induction of Foxm1.
“whereas FXR facilitates liver regeneration via induction of Foxm1.5,60, 61, 62, 63”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [5]
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- Authors
- Huang, W., Ma, K., Zhang, J., Qatanani, M., Cuvillier, J., Liu, J., Dong, B., Huang, X., & Moore, D. D.
- Affiliations
- City Of Hope National Medical Center (US)
- Corresponding author
- Huang, Wendong
- Zhang, Jun
- Qatanani, Mohammed
- Moore, David D.
- ORCID
- Venue
- Science
- Published
- 2006-04-14
- Volume
- 312
- Issue
- 5771
- Pages
- 233-236
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2067834397
- Cited by
- 645
- References
- 3
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 18 · 2023: 23 · 2022: 30 · 2021: 26 · 2020: 36 · 2019: 20 · 2018: 29 · 2017: 40 · 2016: 30 · 2015: 46 · 2014: 40 · 2013: 41 · 2012: 48
- FWCI
- 26.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053366, U19 DK-62434, U19DK062434)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- liver regeneration, bile acids, nuclear receptors, farnesoid X receptor, liver homeostasis, bile acid signaling
- MeSH terms
- Forkhead Box Protein M1, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cell Count, Cholesterol 7-alpha-Hydroxylase, Cholestyramine Resin, Diet, DNA Replication, DNA-Binding Proteins, Gene Expression Regulation, Growth Substances, Hepatectomy, Homeostasis, Liver, Liver Regeneration, RNA, Messenger, Transcription Factors, Signal Transduction, Cytokines, Genes, myc, Proto-Oncogene Proteins c-myc, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Cholic Acid, Hepatocytes, Mice, Forkhead Transcription Factors
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