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

Jia Li-Hawkins, Mats Gåfvels, Maria Olin, Erik G. Lund, Ulla Andersson, Gertrud Schuster, Ingemar Björkhem, David W. Russell, Gosta Eggertsen

Research output: Contribution to journalArticle

153 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1191-1200
Number of pages10
JournalJournal of Clinical Investigation
Volume110
Issue number8
DOIs
StatePublished - Oct 2002

ASJC Scopus subject areas

  • Medicine(all)

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    Li-Hawkins, J., Gåfvels, M., Olin, M., Lund, E. G., Andersson, U., Schuster, G., Björkhem, I., Russell, D. W., & Eggertsen, G. (2002). Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. Journal of Clinical Investigation, 110(8), 1191-1200. https://doi.org/10.1172/JCI0216309