Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTα-OSTβ in cholestasis in humans and rodents

TLDR

OSTα‑OSTβ is a heteromeric bile acid and sterol transporter located at the basolateral membranes of ileum, kidney, and liver epithelium. The study aimed to assess whether OSTα‑OSTβ undergoes FXR‑dependent adaptive regulation after cholestatic liver injury in primary biliary cirrhosis patients and in common bile duct ligation rodent and mouse models. The authors quantified OSTα‑OSTβ mRNA and protein in human PBC samples, CBDL rats, Fxr wild‑type and null mice, and in HepG2 cells stimulated with the FXR ligand chenodeoxycholic acid, using qPCR, Western blot, and confocal microscopy. OSTα‑OSTβ expression is markedly upregulated in cholestasis, with 3‑ to 32‑fold increases in PBC patients and in CBDL animals, and this induction is FXR‑dependent, as evidenced by reduced expression in Fxr null mice and by FXR ligand‑stimulated increases in HepG2 cells.

Abstract

Organic solute transporter (OSTα-OSTβ) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OSTα-OSTβ undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OSTα and OSTβ mRNA increased 3- and 32-fold, respectively, in patients with PBC compared with controls, whereas expression of Ostα and Ostβ also increased in the liver of rats and mice following CBDL. In contrast, expression of Ostα and Ostβ mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ostα and Ostβ compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OSTα and OSTβ mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ostα and Ostβ are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.