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 language | English (US) |
---|---|
Pages (from-to) | 11526-11533 |
Number of pages | 8 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 104 |
Issue number | 28 |
DOIs | |
State | Published - Jul 10 2007 |
Keywords
- Cholesterol turnover
- Lipid metabolism
- Liver disease
- Mouse model
- Nuclear receptor
ASJC Scopus subject areas
- General