Cited by 232Cholesterol and Lipid MetabolismDrug Transport and Resistance MechanismsPharmacogenetics and Drug Metabolism

Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

Li-Hawkins, Jia, Gåfvels, Mats, Olin, Maria, Lund, Erik G., Andersson, Ulla, Schuster, Gertrud, Björkhem, Ingemar, Russell, David W. +1 more·2002·Journal of Clinical Investigation

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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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
  • Health Sciences › Medicine › Surgery › 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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