title: Molecular mechanisms of altered bile acid homeostasis in organic solute transporter-alpha knockout mice.
abstract: OBJECTIVE
  Mutations in the apical sodium-dependent bile acid transporter (SLC10A2) block intestinal bile acid absorption, resulting in a compensatory increase in hepatic bile acid synthesis. Inactivation of the basolateral membrane bile acid transporter (OSTα-OSTβ) also impairs intestinal bile acid absorption, but hepatic bile acid synthesis was paradoxically repressed. We hypothesized that the altered bile acid homeostasis resulted from ileal trapping of bile acids that act via the farnesoid X receptor (FXR) to induce overexpression of FGF15. To test this hypothesis, we investigated whether blocking FXR signaling would reverse the bile acid synthesis phenotype in Ostα null mice.
  
  
  METHODS
  The corresponding null mice were crossbred to generate OstαFxr double-null mice. All experiments compared wild-type, Ostα, Fxr and OstαFxr null littermates. Analysis of the in vivo phenotype included measurements of bile acid fecal excretion, pool size and composition. Hepatic and intestinal gene and protein expression were also examined.
  
  
  RESULTS
  OstαFxr null mice exhibited increased bile acid fecal excretion and pool size, and decreased bile acid pool hydrophobicity, as compared with Ostα null mice. Inactivation of FXR reversed the increase in ileal total FGF15 expression, which was associated with a significant increase in hepatic Cyp7a1 expression.
  
  
  CONCLUSIONS
  Inactivation of FXR largely unmasked the bile acid malabsorption phenotype and corrected the bile acid homeostasis defect in Ostα null mice, suggesting that inappropriate activation of the FXR-FGF15-FGFR4 pathway partially underlies this phenotype. Intestinal morphological changes and reduced apical sodium-dependent bile acid transporter expression were maintained in Ostα(-/-)Fxr(-/-) mice, indicating that FXR is not required for these adaptive responses.
authors.affiliation: Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, N.C., USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Jamie
authors.initials: J
authors.lastname: Haywood
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C476576:organic solute transporter alpha, mouse