Fig. 3.

Mechanisms of FXR regulation of enterohepatic circulation of bile acid. Bile acids synthesized in the liver are excreted into bile via BSEP and stored in the gallbladder. After each meal, bile acids are excreted into the intestinal tract. In the ileum, bile acids are reabsorbed by ASBT in the brush border membrane. Bile acids activate FXR to induce IBABP in enterocytes. OSTα/β transporter in the basolateral membrane effluxes bile acids to portal circulation to hepatocytes where they are taken up by NTCP. In the liver, bile acids activate FXR, which induces SHP expression. SHP then inhibits LRH-1 (or human FTF) and HNF4α transactivation of CYP7A1 (FXR/SHP pathway 1). In the endocrine pathway, intestinal bile acids activate FXR, which induces FGF19 expression. FGF19 may be transported to the liver to activate a liver-specific receptor tyrosine kinase FGFR4 (FXR/FGF19/FGFR4 pathway 2). In the autocrine pathway (pathway 3), cholestatic bile acids may activate FXR and FGF19/FGFR4 signaling, which activates the MAPK/ERK1/2 pathway to inhibit CYP7A1 transcription. It is not clear how the FGF19/ERK1/2 pathway downregulates CYP7A1 transcription. The endocrine pathway may be a physiological pathway for bile acid inhibition of bile acid synthesis, while the autocrine pathway may be an adaptive response to protect liver from cholestatic injury. BARE-II contains 18 bp sequence of overlapping HNF4α and FTF (α-fetoprotein transcription factor, a human homolog of mouse LRH-1) binding site, which is completely conserved in all species.