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J Clin Invest. 2002 Oct;110(8):1191-200.

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

Author information

1
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046, USA.

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 12alpha-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 7alpha-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.

PMID:
12393855
PMCID:
PMC150802
DOI:
10.1172/JCI16309
[Indexed for MEDLINE]
Free PMC Article

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