Figure 3.

Bile acid transport and signaling in the ileum. Luminal BAs are taken up into ileal enterocytes by the apical sodium-dependent bile acid transporter (ASBT), where they are bound by the ileal bile acid-binding protein (IBABP) and transported to the basolateral membrane. BAs are exported basolaterally by the organic solute transporter α/β heterodimer (OSTα/β) and returned to the liver. Intracellular BAs activate the farnesoid X receptor (FXR), which heterodimerizes with the retinoid X receptor (RXR) and translocates to the nucleus. There, FXR transactivates fibroblast growth factor 15/19 (FGF15/19), OSTα/β, and the small heterodimeric partner (SHP). ASBT expression is negatively regulated by SHP within the cell and by an autocrine/paracrine function of FGF15/19, which binds to the FGF receptor 4 (FGFR4)/β-klotho (β-kl) complex and activates signaling processes that repress ASBT. Bile acid diarrhea can be caused by disruptions in these processes. Notably, reduced FGF19 disrupts the negative feedback of bile acid synthesis resulting in bile acid overproduction, while reduced ASBT impairs bile acid absorption.