Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient Mice

Abstract

The bile salt-activated farnesoid X receptor (FXR; NR1H4) controls expression of several genes considered crucial in maintenance of bile salt homeostasis. We evaluated the physiological consequences of FXR deficiency on bile formation and on the kinetics of the enterohepatic circulation of cholate, the major bile salt species in mice. The pool size, fractional turnover rate, synthesis rate, and intestinal absorption of cholate were determined by stable isotope dilution and were related to expression of relevant transporters in the livers and intestines of FXR-deficient (Fxr ؊/؊ ) mice. Fxr ؊/؊ mice showed only mildly elevated plasma bile salt concentrations associated with a 2.4-fold higher biliary bile salt output, whereas hepatic mRNA levels of the bile salt export pump were decreased. Cholate pool size and total bile salt pool size were increased by 67 and 39%, respectively, in Fxr ؊/؊ mice compared with wild-type mice. The cholate synthesis rate was increased by 85% in Fxr ؊/؊ mice, coinciding with a 2.5-fold increase in cholesterol 7␣-hydroxylase (Cyp7a1) and unchanged sterol 12␣-hydroxylase (Cyp8b1) expression in the liver. Despite a complete absence of ileal bile acid-binding protein mRNA and protein, the fractional turnover rate and cycling time of the cholate pool were not affected. The calculated amount of cholate reabsorbed from the intestine per day was ϳ2-fold higher in Fxr ؊/؊ mice than in wild-type mice. Thus, the absence of FXR in mice is associated with defective feedback inhibition of hepatic cholate synthesis, which leads to enlargement of the circulating cholate pool with an unaltered fractional turnover rate. The absence of ileal bile acid-binding protein does not negatively interfere with the enterohepatic circulation of cholate in mice.

Ileal Bile Acid-binding Protein, Functionally Associated with the Farnesoid X Receptor or the Ileal Bile Acid Transporter, Regulates Bile Acid Activity in the Small Intestine

“…These results suggest that I-BABP might be coupled functionally with IBAT without a tight protein-protein interaction. In contrast with these findings, a previous work demonstrated that daily intestinal cholate reabsorption in the FXR Ϫ/Ϫ mice was higher than in wild-type mice despite the complete absence of I-BABP protein in the ilea of the knock-out mice (26), suggesting that I-BABP negatively interferes with the enterohepatic circulation of bile acids. Recently the heteromeric organic solute transporter (Ost)␣-Ost␤ was identified as a basolateral bile acid carrier thought to be responsible for bile salt efflux in ileum (27).…”

Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis

“…However, it remains unclear if ileal bile salt transport mechanisms in rodents operate near maximal capacity. In fact, FXR (Ϫ/Ϫ) mice exhibit over 2-fold increases in biliary bile salt output and intestinal cholate reabsorption, whereas ASBT expression remains unchanged, and ILBP is markedly reduced (37). This suggests that mice possess a significant excess capacity for intestinal bile salt absorption and that the reduced ASBT expression may not interfere with increased enterohepatic bile salt cycling.…”

The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in Mice

“…Different kits were used to determine plasma concentrations of various metabolites: insulin (Mercodia AB), leptin and adiponectin (R&D systems), triglycerides, total, and HDL cholesterol (Roche Applied Science), and FFAs (WAKO). Fat content in feces was measured as previously described (12 Hyperinsulinemic-Euglycemic Clamp Study-These experiments were performed in chronically catheterized, freely moving animals, exactly as described before (13).…”