The Orphan Nuclear Receptor LXRαis Positively and Negatively Regulated by Distinct Products of Mevalonate Metabolism

LXRαis 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 t...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-09, Vol.94 (20), p.10588-10593
Main Authors: Forman, Barry Marc, Ruan, Benfang, Chen, Jasmine, Schroepfer, George J., Evans, Ronald M.
Format: Article
Language:English
Subjects:
Alcohols
Biological Sciences
Biosynthesis
Cholesterols
DNA
Hormone metabolism
Ligands
Metabolism
Nuclear receptors
Orphans
Receptors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:LXRαis 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 LXRαactivity. 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 prophosphate, cholesterol, and oxysterols. Inhibition of LXRαcould be reversed by addition of mevalonic acid and certain oxysterols but not by other products of mevalonic acid metabolism. Surprisingly, the constitutive activity of LXRαwas inhibited by geranylgeraniol, a metabolite of mevalonic acid. These findings suggest that LXRαmay represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of mevalonate metabolism.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.20.10588