RT Journal Article
SR Electronic
T1 Cholesterol Feeding Prevents Hepatic Accumulation of Bile Acids in Cholic Acid-Fed Farnesoid X Receptor (FXR)-Null Mice: FXR-Independent Suppression of Intestinal Bile Acid Absorption
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 338
OP 344
DO 10.1124/dmd.108.022590
VO 37
IS 2
A1 Masaaki Miyata
A1 Yoshiki Matsuda
A1 Masahiro Nomoto
A1 Yuki Takamatsu
A1 Nozomi Sato
A1 Mayumi Hamatsu
A1 Paul A. Dawson
A1 Frank J. Gonzalez
A1 Yasushi Yamazoe
YR 2009
UL http://dmd.aspetjournals.org/content/37/2/338.abstract
AB Cholic acid (CA) feeding of farnesoid X receptor (Fxr)-null mice results in markedly elevated hepatic bile acid levels and liver injury. In contrast, Fxr-null mice fed cholesterol plus CA (CA+Chol) do not exhibit liver injury, and hepatic bile acid levels and bile acid pool size are reduced 51 and 40%, respectively, compared with CA-treated Fxr-null mice. These decreases were not observed in wild-type mice. Despite a reduced bile acid pool size, hepatic Cyp7a1 mRNA expression was increased in Fxr-null mice fed the CA+Chol diet, and biliary bile acid output was not changed. Analysis of other potential protective mechanisms revealed significant decreases in portal blood bile acid concentrations and a reduced ileal bile acid absorption capacity, as estimated using an in situ loop method. Fecal bile acid excretion was also increased in Fxr-null mice fed the CA+Chol versus CA diet. The decreased ileal bile acid absorption correlated with decreased ileal apical sodium-dependent bile salt transporter (ASBT) protein expression in brush-border membranes. These results suggest a critical role for ileal bile acid absorption in regulation of hepatic bile acid levels in Fxr-null mice fed CA+Chol. Furthermore, experiments with Fxr-null mice suggest that cholesterol feeding can down-regulate ASBT expression through a pathway independent of FXR. U.S. Government work not protected by U.S. copyright.