Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Nuclear receptors (NRs) regulate gene expression and physiology.
• Estrogen-related receptor alpha (ERRα) is a key NR involved in cancer, metabolism, and skeletal homeostasis.
• Many NRs, including ERRα, lack identified natural activators.

Purpose of the Study:

• To identify endogenous ligands for estrogen-related receptor alpha (ERRα).
• To investigate the functional relationship between cholesterol and ERRα.
• To elucidate the role of ERRα in the mechanisms of action for statins and bisphosphonates.

Main Methods:

• Affinity chromatography using the ERRα ligand-binding domain (LBD) to analyze tissue lipidomes.
• Transcriptional assays to confirm ligand activity.
• Studies using ERRα knockout mice and pharmacological inhibition.

Main Results:

• Cholesterol was identified as an endogenous agonist for ERRα.
• Cholesterol's effects on bone, muscle, and macrophage function are dependent on ERRα.
• ERRα mediates the impact of cholesterol, statins, and bisphosphonates on cellular processes.

Conclusions:

• Cholesterol is a direct endogenous ligand for ERRα, revealing a critical regulatory mechanism.
• ERRα mediates the physiological effects of cholesterol and influences the action of major drugs.
• This discovery provides insights into cholesterol metabolism, bone homeostasis, and drug-induced toxicities.