Figure 2.

Under specific circumstances which remain unclear the Farnesoid X receptor (FXR) may be stimulated in the gastrointestinal tract. There is some evidence from a single human probiotic study that FXR may be stimulated through BSH activity but further studies are warranted. (A) In a model where gastrointestinal FXR is stimulated unconjugated bile acids (UC-BA) may access the FXR through non-specific passage through cell membranes. (B) There is good evidence that intestinal FXR activation promotes the Transintestinal Cholesterol Excretion (TICE) system for the net efflux of cholesterol into the feces. FXR activation leads to elevated intestinal production of FGF15/19 which feeds back to inhibit bile acid synthesis. Via a process that involves FXR this results in a net reduction in hydrophobic BA species but a relative increase in hydrophilic BA species which are released into the small intestine. As hydrophilic BAs poorly associate with cholesterol this may reduce cellular uptake of cholesterol in the gut. (C) There is also good evidence that elevated hepatic FXR activation increases systemic reverse cholesterol transport (RCT) for the mobilization of cholesterol from macrophages (as HDL-C) to the liver for excretion. (D) There is evidence to suggest that engagement of the FXR reduces the secretion of VLDL into the circulation thereby reducing the systemic circulation of this atherogenic molecule. (E) There is also evidence to suggest that engagement of the FXR increases the uptake of LDL into the liver from the circulation thereby reducing the systemic circulation of this atherogenic molecule. (F) Finally, there is evidence to suggest that FXR activation increases hepatic ABCG5/8 with potential to promote biliary secretion of cholesterol.