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

Abstract

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 25, 2006. 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 3␣-hydroxyl group. Here, we characterize a line of knockout mice that cannot epimerize the 3␤-hydroxyl group of cholesterol and as a consequence synthesize a bile acid pool in which 3␤-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.cholesterol turnover ͉ lipid metabolism ͉ liver disease ͉ mouse model ͉ nuclear receptor

MALDI imaging MS reveals candidate lipid markers of polycystic kidney disease

“…The position of the proposed double bond in m/z 512.3 cannot be inferred from these studies. However, it may be at C-5 ( 36 ). For validation of the unusually high m/z 514.3 levels in neonate PCK and SDR rat livers (i.e., to rule out an interfering, unresolved analyte), we compared fragments of this precursor ion in 0-week-old livers with fragments of the same m/z in urine of 10-week-old PCK rats by MALDI-TOF/ TOF MS (supplementary Fig.…”

“…IV-A). It is tempting to speculate that the observed biphasic behavior of m/z 514.3 in liver might be explained by changes in homeostasis of cholesterol-oxidoreductase enzyme activities during rat development ( 36 ).…”

Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs

“…3E; Shea et al 2007;Le Martelot et al 2009;Guillou et al 2010;Sayin et al 2013). Predicted activity of ELF oscillated and peaked near ZT3 in WT liver but was flat in Bmal1 KO ( Fig.…”

The organic solute transporter α-β, Ostα-Ostβ, is essential for intestinal bile acid transport and homeostasis

“…These results suggest that the normal homeostatic regulation of hepatic bile acid synthesis is altered in Ost␣ Ϫ/Ϫ mice. Because intestinal cholesterol absorption is particularly sensitive to variations in bile acid pool size and composition (19)(20)(21), we also examined neutral sterol excretion in Ost␣ Ϫ/Ϫ mice. Fecal cholesterol excretion was elevated Ϸ4-fold in both male and female Ost␣ Ϫ/Ϫ mice (Fig.…”