A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
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Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
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Bile acids act as ligands for FXR, which indirectly suppresses Cyp7A1, the rate-limiting enzyme in bile acid biosynthesis.
“bile acids act as ligands for the farnesoid X receptor (FXR, NR1H4), which then indirectly suppresses Cyp7A1, the rate limiting enzyme in bile acid biosynthesis (Goodwin et al., 2000).”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Goodwin et al., 2000
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- Authors
- Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., Maloney, P. R., Willson, T. M., & Kliewer, S. A.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Kliewer, Steven A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 6
- Issue
- 3
- Pages
- 517-526
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1990819179
- Cited by
- 1,940
- References
- 51
- Citations by year
- 2026: 68 · 2025: 70 · 2024: 89 · 2023: 78 · 2022: 80 · 2021: 107 · 2020: 81 · 2019: 86 · 2018: 79 · 2017: 77 · 2016: 65 · 2015: 69 · 2014: 66 · 2013: 76 · 2012: 71
- FWCI
- 27.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- bile acid synthesis, farnesoid X receptor, LRH-1, CYP7A1, transcriptional repression, nuclear receptors, orphan nuclear receptor, regulatory cascade
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cells, Cultured, Cholesterol 7-alpha-Hydroxylase, DNA-Binding Proteins, Humans, Male, Promoter Regions, Genetic, Rats, Inbred F344, Repressor Proteins, RNA, Messenger, Transcription Factors, Transfection, Blotting, Northern, Gene Expression Regulation, Enzymologic, Protein Tyrosine Phosphatases, Receptors, Cytoplasmic and Nuclear, Hepatocytes, Intracellular Signaling Peptides and Proteins, Rats, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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