Analysis of HSD3B7 knockout mice reveals that a 3α-hydroxyl stereochemistry is required for bile acid function

Heidi C. Shea, Daphne D. Head, Kenneth D R Setchell, David W. Russell

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Primary bile acids are synthesized from cholesterol in the liver and thereafter are secreted into the bile and small intestine. Gut flora modify primary bile acids to produce secondary bile acids leading to a chemically diverse bile acid pool that is circulated between the small intestine and liver. A majority of primary and secondary bile acids in higher vertebrates have a 3α-hydroxyl group. Here, we characterize a line of knockout mice that cannot epimerize the 3β-hydroxyl group of cholesterol and as a consequence synthesize a bile acid pool in which 3β-hydroxylated bile acids predominate. This alteration causes death in 90% of newborn mice and decreases the absorption of dietary cholesterol in surviving adults. Negative feedback regulation of bile acid synthesis mediated by the farnesoid X receptor (FXR) is disrupted in the mutant mice. We conclude that the correct stereochemistry of a single hydroxyl group at carbon 3 in bile acids is required to maintain their physiologic and regulatory functions in mammals.

Original languageEnglish (US)
Pages (from-to)11526-11533
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number28
DOIs
StatePublished - Jul 10 2007

Keywords

  • Cholesterol turnover
  • Lipid metabolism
  • Liver disease
  • Mouse model
  • Nuclear receptor

ASJC Scopus subject areas

  • General

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