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Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice
Open accessAbstract
UNLABELLED: Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile-acid synthesis by reducing the expression levels of genes encoding key bile-acid synthetic enzymes (e.g., cytochrome P450 [CYP]7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR-mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15; FGF19 in humans) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression, and the associated cell-signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal-related kinase (ERK) and, to a smaller degree, Jun N-terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15-mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15-mediated suppression of Cyp7a1 and Cyp8b1 gene expression. CONCLUSION: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating the expression of genes critical for bile-acid synthesis and hydrophobicity in the liver.
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“Intestinal Fgf15 is a potent inhibitor of Cyp7a1 expression and BA synthesis (Kong et al., 2012).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Kong et al., 2012
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Metadata
- Authors
- Kong, B., Wang, L., Chiang, J. Y. L., Zhang, Y., Klaassen, C. D., & Guo, G. L.
- Affiliations
- University of Kansas Medical Center (US)
- University of Utah (US)
- Northeast Ohio Medical University (US)
- Corresponding author
- Guo, Grace L.
- Venue
- Hepatology
- Published
- 2012-09
- Volume
- 56
- Issue
- 3
- Pages
- 1034-1043
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3390456
- OpenAlex
- W2046811888
- Cited by
- 456
- References
- 33
- Citations by year
- 2026: 31 · 2025: 36 · 2024: 34 · 2023: 51 · 2022: 41 · 2021: 37 · 2020: 30 · 2019: 28 · 2018: 36 · 2017: 33 · 2016: 25 · 2015: 24 · 2014: 28 · 2013: 16 · 2012: 5
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01dk044442-26)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080440, DK-081343, R56DK090036, R01-DK-044442, R01DK081343, R01DK44442, R37DK058379)
- National Center for Research Resources (P20RR021940)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- farnesoid X receptor, bile acid synthesis, CYP7A1, CYP8B1, small heterodimer partner, FGF15, FGF19, ERK signaling, JNK signaling, tissue-specific gene regulation
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Gene Expression, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mice
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