title: Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism.
abstract: OBJECTIVE
  Blocking intestinal bile acid (BA) absorption by inhibiting or inactivating the apical sodium-dependent BA transporter (Asbt) classically induces hepatic BA synthesis. In contrast, blocking intestinal BA absorption by inactivating the basolateral BA transporter, organic solute transporter alpha-beta (Ostα-Ostβ) is associated with an altered homeostatic response and decreased hepatic BA synthesis. The aim of this study was to determine the mechanisms underlying this phenotype, including the role of the farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15).
  
  
  METHODS
  BA and cholesterol metabolism, intestinal phenotype, expression of genes important for BA metabolism, and intestinal FGF15 expression were examined in wild type, Ostα(-/-), Fxr(-/-), and Ostα(-/-)Fxr(-/-) mice.
  
  
  RESULTS
  Inactivation of Ostα was associated with decreases in hepatic cholesterol 7α-hydroxylase (Cyp7a1) expression, BA pool size, and intestinal cholesterol absorption. Ostα(-/-) mice exhibited significant small intestinal changes, including altered ileal villus morphology, and increases in intestinal length and mass. Total ileal FGF15 expression was elevated almost 20-fold in Ostα(-/-) mice as a result of increased villus epithelial cell number and ileocyte FGF15 protein expression. Ostα(-/-)Fxr(-/-) mice exhibited decreased ileal FGF15 expression, restoration of intestinal cholesterol absorption, and increases in hepatic Cyp7a1 expression, fecal BA excretion, and BA pool size. FXR deficiency did not reverse the intestinal morphological changes or compensatory decrease for ileal Asbt expression in Ostα(-/-) mice.
  
  
  CONCLUSIONS
  These results indicate that signaling via FXR is required for the paradoxical repression of hepatic BA synthesis but not the complex intestinal adaptive changes in Ostα(-/-) mice.
authors.affiliation: Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.forename: Jamie
authors.initials: J
authors.lastname: Haywood
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kock
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D005346:Fibroblast Growth Factors; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C476576:organic solute transporter alpha, mouse; C502772:Cyp7a1 protein, mouse