Figure 1.

The FXR in regulation of the enterohepatic circulation. Bile acids (BAs) are synthesized in the hepatocyte by CYP7A1 and secreted into the enterohepatic circulation (orange arrows) by the bile salt export pump (BSEP). In ileal enterocytes, BAs are absorbed through the ASBT, bind to the ileal bile acid binding protein (IBABP), and are pumped into the portal circulation by the basolateral organic solute transporter (OST)α-OSTβ dimer. BAs are taken back up into hepatocytes by the Na⁺-taurocholate co-transporting polypeptide (NTCP). Treatment with FXR agonists (blue lines) induces expression of short heterodimeric partner (SHP) in the liver and of FGF19, IBABP, OSTα-OSTβ, and SHP in ileal enterocytes. FGF19 enters the portal circulation and acts on FGF receptor 4–Klothoβ receptors in hepatocytes (purple arrows) to inhibit CYP7A1 expression. SHP also down-regulates CYP7A1 expression in hepatocytes, further dampening BA synthesis. With each cycle of the EHC, a small proportion of the bile acid pool enters the colon where it is metabolized by the resident microbiota into deconjugated secondary bile acids. In primary BAD, impaired FGF19 production results in increased CYP7A1 expression and enhanced hepatic synthesis of bile acids. In turn, this results in a larger bile acid pool with increased colonic delivery.