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Cholic acid mediates negative feedback regulation of bile acid synthesis in mice
Abstract
Cholesterol is converted into dozens of primary and secondary bile acids through pathways subject to negative feedback regulation mediated by the nuclear receptor farnesoid X receptor (FXR) and other effectors. Disruption of the sterol 12α-hydroxylase gene (Cyp8b1) in mice prevents the synthesis of cholate, a primary bile acid, and its metabolites. Feedback regulation of the rate-limiting biosynthetic enzyme cholesterol 7α-hydroxylase (CYP7A1) is lost in Cyp8b1–/– mice, causing expansion of the bile acid pool and alterations in cholesterol metabolism. Expression of other FXR target genes is unaltered in these mice. Cholate restores CYP7A1 regulation in vivo and in vitro. The results implicate cholate as an important negative regulator of bile acid synthesis and provide preliminary evidence for ligand-specific gene activation by a nuclear receptor.
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“and Cyp8b1 KO (sgCyp8b1) decreased the levels of TCA, as expected (23).”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [23]
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“This process is controlled by a negative-feedback loop through the activation of the nuclear farnesoid X receptor (FXR) in the ileum and liver (7, 8).”
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Cites
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Cited by
Sorted by citations
Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism
Wahlstrom, A. M., Sayin, S. I., Marschall, H., & Bäckhed, F. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.005 · Cited by 2,969
Sayin, S. I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H.-U., Bamberg, K., Angelin, B., Hyötyläinen, T., Orešič, M., & Bäckhed, F. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.01.003 · Cited by 2,331
The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
Russell, D. W. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161712 · Cited by 2,069
Self-citationTargeting bile‐acid signalling for metabolic diseases
Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J., & Schoonjans, K. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2619 · Cited by 1,422
Chen, M.-L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J., Zhu, J.-D., Zhang, Q.-Y., & Mi, M.-T. (2016) · mBio · doi:10.1128/mbio.02210-15 · Cited by 754
“the nuclear farnesoid X receptor (FXR) in the ileum and liver (7, 8).”
Background
Metadata
- Authors
- Li-Hawkins, J., Gåfvels, M., Olin, M., Lund, E. G., Andersson, U., Schuster, G., Björkhem, I., Russell, D. W., & Eggertsen, G.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Karolinska Institutet (SE)
- Corresponding author
- Russell, David W.
- Venue
- Journal of Clinical Investigation
- Published
- 2002-10-15
- Volume
- 110
- Issue
- 8
- Pages
- 1191-1200
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4239553605
- Cited by
- 227
- References
- 45
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 16 · 2020: 21 · 2019: 12 · 2018: 16 · 2017: 7 · 2016: 12 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 9
- FWCI
- 8.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- W. M. Keck Foundation
- National Institutes of Health (HL20948)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- cholic acid, cholate, bile acid synthesis, negative feedback regulation, farnesoid X receptor, CYP8B1, sterol 12alpha-hydroxylase, CYP7A1, cholesterol metabolism
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