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

作者：Lan Tian; Rao Anuradha; Haywood Jamie; Kock Nancy D; Dawson Paul A^*

来源：Journal of Hepatology, 2012, 57(2): 359-365.

DOI：10.1016/j.jhep.2012.03.025

• Bile acids
• Enterohepatic circulation
• Transporters
• Cholesterol
• Cyp7a1
• FXR

Background %26 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 (Ost alpha-Ost beta) 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). %26lt;br%26gt;Methods: BA and cholesterol metabolism, intestinal phenotype, expression of genes important for BA metabolism, and intestinal FGF15 expression were examined in wild type, Ost alpha(-/-), Fxr(-/-), and Ost alpha(-/-) Fxr(-/-) mice. %26lt;br%26gt;Results: Inactivation of Ost alpha was associated with decreases in hepatic cholesterol 7 alpha-hydroxylase (Cyp7a1) expression, BA pool size, and intestinal cholesterol absorption. Ost alpha(-/-) 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 Ost alpha(-/-) mice as a result of increased villus epithelial cell number and ileocyte FGF15 protein expression. Ost alpha(-/-) 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 Ost alpha(-/-) mice. %26lt;br%26gt;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 Ost alpha(-/-) mice.

• 出版日期2012-8