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 superfam ily that displays constitutive transcriptional activity, We reasoned t hat this activity may result from the production of an endogenous acti vator that is a component of intermediary metabolism. The use of metab olic 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 nu mber of important molecules including farnesyl pyrophosphate, geranylg eranyl pyrophosphate, cholesterol, and oxysterols. Inhibition of LXR a lpha could be reversed by addition of mevalonic acid and certain oxyst erols but not by other products of mevalonic acid metabolism. Surprisi ngly, the constitutive activity of LXR alpha was inhibited bg geranylg eraniol, a metabolite of mevalonic acid, These findings suggest that L XR alpha may represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of m evalonate metabolism.