The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism.
LXRalpha 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 LXRalpha 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 LXRalpha 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 LXRalpha was inhibited by geranylgeraniol, a metabolite of mevalonic acid. These findings suggest that LXRalpha may represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of mevalonate metabolism.
Forman
B M
BM
The Salk Institute for Biological Studies, Gene Expression Lab, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Forman@axp1.Salk.edu
Ruan
B
B
Chen
J
J
Schroepfer
G J
GJ
Evans
R M
RM
D002460:Cell Line; D004268:DNA-Binding Proteins; D004224:Diterpenes / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D008798:Mevalonic Acid / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism
D004268:DNA-Binding Proteins; D004224:Diterpenes; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; C017338:geranylgeraniol; D008798:Mevalonic Acid