New targets in and potential treatments for cholesterol gallstone disease.

Gallstone disease is very common among American Indians and Hispanics, and approximately 20 million patients are treated for this disease annually in the US. Bile acid receptor (nuclear farnesoid X receptor; FXR) knockout mice fed a lithogenic diet are more susceptible to gallstone disease than wild-type mice. The C57L mouse is also susceptible to gallstone formation when fed a lithogenic diet, and in this model, the small-molecule FXR agonist GW-4064 prevents the precipitation of cholesterol. Bile acids (eg, P-muricholic acid) and their derivatives are also being developed as FXR agonists. Fatty acid bile acid conjugates have the potential to prevent and reverse cholesterol crystallization. Furthermore, agents that increase the expression of selected hepatocyte bile acid transporters may also be useful in the treatment of gall bladder disease.