Bile acids, farnesoid X receptor, atherosclerosis and metabolic control

Bile acids are amphiphilic molecules synthesized from cholesterol exclusively in the liver that are essential for effective absorption of dietary fat. In addition to this 'classical role', bile acids act as signalling molecules that control their own metabolism by activating the nuclear receptor, farnesoid X receptor.

Recent work demonstrates that farnesoid X receptor exerts metabolic control beyond bile acid homeostasis, notably effects on HDL, triglyceride and glucose metabolism. Farnesoid X receptor influences insulin sensitivity of tissues that are not part of the enterohepatic circulation, for example, adipose tissue. Certain metabolic effects in the liver appear to be mediated via farnesoid X receptor-stimulated release of an intestinal growth factor. In addition, novel signalling pathways independent of farnesoid X receptor have been identified that may contribute to bile acid-mediated metabolic regulation.

Farnesoid X receptor represents a potentially attractive target for treatment of various aspects of the metabolic syndrome and for prevention of atherosclerosis. Yet, in view of its pleiotropic effects and apparent species-specificity, it is evident that successful interference of the farnesoid X receptor signalling system will require the development of gene-specific and/or organ-specific farnesoid X receptor modulators and extensive testing in human models of disease.