Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich‐cultured human hepatocytes

Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100‐fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich‐cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose‐dependently increased fibroblast growth factor‐19 (FGF‐19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7‐alpha‐hydroxylase (CYP7A1), the rate‐limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8‐fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OST (α)) and OST (β) increased by 6.4 ± 0.2‐fold and 42.9 ± 7.9‐fold, respectively. The upregulation of BSEP and OST (α) and OST (β,) by OCA reduced the intracellular concentrations of d(8)‐TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid‐induced toxicity observed in cholestatic diseases.