A model for farnesoid feedback control in the mevalonate pathway.

ABSTRACT

Mevalonate is the rate-limiting substrate leading to farnesyl pyrophosphate (FPP), the central intermediate for isoprenoids such as cholesterol, dolichols, ubiquinone, and carotenoids. One major challenge has been to identify the isoprenoid effector molecules and transcription factors mediating negative regulation in this metabolic pathway. A nuclear receptor called FXR has recently been characterized that is activated by farnesyl pyrophosphate metabolites such as farnesol, farnesal, farnesoic acid, and methyl farnesoate. FXR expression in isoprenoidogenic tissues suggests a hypothesis that these intracellular "farnesoids" may be signals for transcriptional feedback control of cholesterol biosynthesis.