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

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.

Ostα−/−mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity

“…In 5-and 12-mo-old mice, mRNAs encoding the apical cholesterol uptake transporter Niemann-Pick C1-like 1 (Npc1L1) in the distal intestinal segment and the basolateral cholesterol efflux transporter ATPbinding cassette transporter 1 (Abca1) in each intestinal section were lower in Ost␣ Ϫ/Ϫ mice, in agreement with a previous study of ileal Npc1L1 and Abca1 in 3-mo-old male mice (13).…”

“…However, Ibabp expression was by far the highest in the distal small intestine (Table 3). Because the small intestine was sectioned into equal thirds and Ost␣ Ϫ/Ϫ mice have elongated ileums and relatively normal-length jejunums and duodenums (13), there was probably more ileal tissue in the middle sections of small intestine from Ost␣ Ϫ/Ϫ mice, accounting for the apparent increase in Ibabp expression in those sections.…”

“…The mechanism for the growth delay in Ost␣ Ϫ/Ϫ mice is unknown. The small intestine is longer and heavier in Ost␣ Ϫ/Ϫ than wild-type mice, with apparent ileal enterocyte dysplasia (1,13,25,32). Ost␣ Ϫ/Ϫ mice exhibit impaired transileal bile acid absorption coupled with an increase in ileal FGF15 production and a decrease in hepatic Cyp7a1 expression resulting from activation of the FXR in the ileocyte (1,12,13,25).…”

“…Ost␣ Ϫ/Ϫ mice exhibit impaired transileal bile acid absorption coupled with an increase in ileal FGF15 production and a decrease in hepatic Cyp7a1 expression resulting from activation of the FXR in the ileocyte (1,12,13,25). Ost␣ Ϫ/Ϫ mice have a markedly reduced bile acid pool size and decreased cholesterol and lipid absorption (1,13,25).…”

Intestinal transport and metabolism of bile acids

“…Additional insight to the in vivo functions of OST ␣ -OST ␤ comes from a study of OST ␣ -null mice lacking FXR ( 108 ). In that study, loss of FXR in OST ␣ -null mice restored intestinal cholesterol absorption and reversed the decreases in hepatic bile acid synthesis, fecal bile acid excretion, and bile acid pool size.…”