24(S),25-Epoxycholesterol: A messenger for cholesterol homeostasis

The oxysterol 24(S),25-epoxycholesterol is made in a shunt in the cholesterol biosynthetic pathway in all cholesterogenic cells. Evidence is emerging that endogenous 24(S),25-epoxycholesterol can work at several levels to control acute cholesterol homeostasis. For instance, this oxysterol suppresses activation of the master regulators of cholesterol homeostasis, the sterol regulatory element binding proteins. Indeed, 24(S),25-epoxycholesterol appears to serve as a measure of cholesterol synthesis and to protect against surges in the production of this potentially cytotoxic molecule. In addition, endogenous 24(S),25-epoxycholesterol is a natural ligand for the liver X receptors which induce expression of cholesterol efflux-related genes. Levels of endogenous 24(S),25-epoxycholesterol can be artificially elevated by partially inhibiting the step after the start of the shunt, catalysed by oxidosqualene cyclase. The idea of manipulating a self-governing pathway for the production of a physiological regulator, that can enhance cholesterol removal and decrease uptake and synthesis, is attractive and warrants further evaluation.