PT - JOURNAL ARTICLE AU - Masaaki Miyata AU - Yoshiki Matsuda AU - Masahiro Nomoto AU - Yuki Takamatsu AU - Nozomi Sato AU - Mayumi Hamatsu AU - Paul A. Dawson AU - Frank J. Gonzalez AU - Yasushi Yamazoe TI - 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 AID - 10.1124/dmd.108.022590 DP - 2009 Feb 01 TA - Drug Metabolism and Disposition PG - 338--344 VI - 37 IP - 2 4099 - http://dmd.aspetjournals.org/content/37/2/338.short 4100 - http://dmd.aspetjournals.org/content/37/2/338.full SO - Drug Metab Dispos2009 Feb 01; 37 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.