The orphan nuclear receptor LXR alpha is positively and negatively regulated by distinct products of mevalonate metabolism

LXR alpha is an orphan member of the nuclear hormone receptor superfamily that displays constitutive transcriptional activity, We reasoned that this activity may result from the production of an endogenous activator that is a component of intermediary metabolism. The use of metabolic inhibitors revealed that mevalonic acid biosynthesis is required for LXR alpha activity, Mevalonic acid is a common metabolite used by virtually all eukaryotic cells. It serves as a precursor to a large number of important molecules including farnesyl pyrophosphate, geranylgeranyl pyrophosphate, cholesterol, and oxysterols. Inhibition of LXR alpha could be reversed by addition of mevalonic acid and certain oxysterols but not by other products of mevalonic acid metabolism. Surprisingly, the constitutive activity of LXR alpha was inhibited bg geranylgeraniol, a metabolite of mevalonic acid, These findings suggest that LXR alpha may represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of mevalonate metabolism.