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.
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.
Miyata
Masaaki
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp
Matsuda
Yoshiki
Y
Nomoto
Masahiro
M
Takamatsu
Yuki
Y
Sato
Nozomi
N
Hamatsu
Mayumi
M
Dawson
Paul A
PA
Gonzalez
Frank J
FJ
Yamazoe
Yasushi
Y
D000042:Absorption / Q000187:drug effects; D000821:Animal Feed; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D002784:Cholesterol / Q000494:pharmacology*; D019826:Cholic Acid / Q000378:metabolism; D005260:Female; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D017093:Liver Failure / Q000175:diagnosis* / Q000378:metabolism; D008297:Male; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism
D001647:Bile Acids and Salts; D015415:Biomarkers; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D011987:Receptors, Steroid; D027981:Symporters; C035417:cholic acid receptor; C071908:sodium-bile acid cotransporter; D002784:Cholesterol; D019826:Cholic Acid