title: Muricholic bile acids are potent regulators of bile acid synthesis via a positive feedback mechanism.
abstract: OBJECTIVE
  Bile acid (BA) synthesis is regulated by negative feedback end-product inhibition, initiated by farnesoid X receptors (FXRs) in liver and gut. Studies on cholic acid (CA)-free Cyp8b1(-/-) mice have concluded that CA is a potent suppressor of BA synthesis. Cyp8b1(-/-) mice have increased BA synthesis and an enlarged BA pool, a phenotype shared with bile-duct-ligated, antibiotics-administered and with germ-free mice. Studies on such mice have concluded BA synthesis is induced due to reduced hormonal signalling by fibroblast growth factor (FGF)15 from intestine to liver. A mutual finding in these models is that potent FXR-agonistic BAs are reduced. We hypothesized that the absence of the potent FXR agonist deoxycholic acid (DCA) may be important for the induction of BA synthesis in these situations.
  
  
  METHODS
  Two of these models were investigated, antibiotic treatment and Cyp8b1(-/-) mice and their combination. Secondary BA formation was inhibited by ampicillin (AMP) given to wild-type and Cyp8b1(-/-) mice. We then administered CA, chenodeoxycholic acid (CDCA) or DCA to AMP-treated Cyp8b1(-/-) mice.
  
  
  RESULTS
  Our data show that the phenotype of AMP-treated wild-type mice resembles that of Cyp8b1(-/-) mice with fourfold induced Cyp7a1 expression, increased intestinal apical sodium-dependent BA transporter expression and increased hepatic BA levels. We also show that reductions in the FXR-agonistic BAs CDCA, CA, DCA or lithocholic acid cannot explain this phenotype; instead, it is likely due to increases in levels of α- and β-muricholic BAs and ursodeoxycholic acid, three FXR-antagonistic BAs.
  
  
  CONCLUSIONS
  Our findings reveal a potent positive feedback mechanism for regulation of BA synthesis in mice that appears to be sufficient without endocrine effects of FGF15 on Cyp7a1. This mechanism will be fundamental in understanding BA metabolism in both mice and humans.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Bonde
authors.forename: G
authors.initials: G
authors.lastname: Eggertsen
authors.forename: M
authors.initials: M
authors.lastname: Rudling
mesh_terms: D000667:Ampicillin / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002793:Cholic Acids / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000667:Ampicillin; D000900:Anti-Bacterial Agents; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D002793:Cholic Acids; D005346:Fibroblast Growth Factors; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C071908:sodium-bile acid cotransporter; C004821:muricholic acid
keywords: antagonist; apical sodium-dependent bile acid transporter; fibroblast growth factor 15; muricholic acid; steroid 12-alpha hydroxylase