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.
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.
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, Sendai, 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp
Masaaki
M
Miyata
Aki
A
Tozawa
Hijiri
H
Otsuka
Toshifumi
T
Nakamura
Kiyoshi
K
Nagata
Frank J
FJ
Gonzalez
Yasushi
Y
Yamazoe
D000255:Adenosine Triphosphate / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology / Q000517:prevention & control*; D019826:Cholic Acid / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008111:Liver Function Tests; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013654:Taurine / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase; D001219:Aspartate Aminotransferases; D001647:Bile Acids and Salts; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013654:Taurine; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated