Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism

J Hepatol. 2012 Aug;57(2):359-65. doi: 10.1016/j.jhep.2012.03.025. Epub 2012 Apr 25.

Abstract

Background & aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Cholesterol / metabolism
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Fibroblast Growth Factors / genetics*
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Male
  • Membrane Transport Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear / physiology

Substances

  • Bile Acids and Salts
  • Membrane Transport Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • fibroblast growth factor 15, mouse
  • organic solute transporter alpha, mouse
  • farnesoid X-activated receptor
  • Fibroblast Growth Factors
  • Cholesterol
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse