The organic solute transporter α-β, Ostα-Ostβ, is essential for intestinal bile acid transport and homeostasis

TLDR

The apical sodium‑dependent bile acid transporter (Asbt) mediates intestinal uptake, but the basolateral exporter remains unidentified, and the heteromeric organic solute transporter Ostα‑Ostβ has been proposed as a candidate yet its in vivo role is unknown. The study aimed to determine the role of Ostα‑Ostβ in intestinal bile acid absorption. This was achieved by disrupting the Ostα gene via homologous recombination in mice. Ostα‑deficient mice displayed normal appearance but exhibited >80 % reduction in ileal taurocholate transport, a >65 % decrease in bile acid pool size without increased fecal excretion, reduced hepatic Cyp7a1 expression inversely correlated with ileal FGF15, and overall evidence that Ostα‑Ostβ is essential for intestinal bile acid transport and disrupts hepatic bile acid biosynthesis homeostasis.

Abstract

The apical sodium-dependent bile acid transporter (Asbt) is responsible for transport across the intestinal brush border membrane; however, the carrier(s) responsible for basolateral bile acid export into the portal circulation remains to be determined. Although the heteromeric organic solute transporter Ostalpha-Ostbeta exhibits many properties predicted for a candidate intestinal basolateral bile acid transporter, the in vivo functions of Ostalpha-Ostbeta have not been investigated. To determine the role of Ostalpha-Ostbeta in intestinal bile acid absorption, the Ostalpha gene was disrupted by homologous recombination in mice. Ostalpha(-/-) mice were physically indistinguishable from wild-type mice. In everted gut sac experiments, transileal transport of taurocholate was reduced by >80% in Ostalpha(-/-) vs. wild-type mice; the residual taurocholate transport was further reduced to near-background levels in gut sacs prepared from Ostalpha(-/-)Mrp3(-/-) mice. The bile acid pool size was significantly reduced (>65%) in Ostalpha(-/-) mice, but fecal bile acid excretion was not elevated. The decreased pool size in Ostalpha(-/-) mice resulted from reduced hepatic Cyp7a1 expression that was inversely correlated with ileal expression of fibroblast growth factor 15 (FGF15). These data indicate that Ostalpha-Ostbeta is essential for intestinal bile acid transport in mice. Unlike a block in intestinal apical bile acid uptake, genetic ablation of basolateral bile acid export disrupts the classical homeostatic control of hepatic bile acid biosynthesis.