TY - JOUR T1 - Role of Farnesoid X Receptor in the Enhancement of Canalicular Bile Acid Output and Excretion of Unconjugated Bile Acids: A Mechanism for Protection against Cholic Acid-Induced Liver Toxicity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 759 LP - 766 DO - 10.1124/jpet.104.076158 VL - 312 IS - 2 AU - Masaaki Miyata AU - Aki Tozawa AU - Hijiri Otsuka AU - Toshifumi Nakamura AU - Kiyoshi Nagata AU - Frank J. Gonzalez AU - Yasushi Yamazoe Y1 - 2005/02/01 UR - http://jpet.aspetjournals.org/content/312/2/759.abstract N2 - Mice lacking the farnesoid X receptor (FXR) involved in the maintenance of hepatic bile acid levels are highly sensitive to cholic acid-induced liver toxicity. Serum aspartate aminotransferase (AST) activity was elevated 15.7-fold after feeding a 0.25% cholic acid diet, whereas only slight increases in serum AST (1.7- and 2.5-fold) were observed in wild-type mice fed 0.25 and 1% cholic acid diet, respectively. Bile salt export pump mRNA and protein levels were increased in wild-type mice fed 1% cholic acid diet (2.1- and 3.0-fold) but were decreased in FXR-null mice fed 0.25% cholic acid diet. The bile acid output rate was 2.0- and 3.7-fold higher after feeding of 0.25 and 1.0% cholic acid diet in wild-type mice, respectively. On the other hand, no significant increase in bile acid output rate was observed in FXR-null mice fed 0.25% cholic acid diet in contrast to a significant decrease observed in mice fed a 1.0% cholic acid diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. Unconjugated cholic acid was not detected in the bile of wild-type mice fed a control diet, but it was readily detected in wild-type mice fed 1% cholic acid diet. The ratio of biliary unconjugated cholic acid to total cholic acid (unconjugated cholic acid and tauro-conjugated cholic acid) reached 30% under conditions of hepatic taurine depletion. These results suggest that the cholic acid-induced enhancement of canalicular bile acid output rates and excretion of unconjugated bile acids are involved in adaptive responses for prevention of cholic acid-induced toxicity. ER -