Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects

Cell Metab. 2016 Mar 8;23(3):479-91. doi: 10.1016/j.cmet.2015.12.010. Epub 2016 Jan 14.


Nuclear receptors (NRs) are key regulators of gene expression and physiology. Nearly half of all human NRs lack endogenous ligands including estrogen-related receptor α (ERRα). ERRα has important roles in cancer, metabolism, and skeletal homeostasis. Affinity chromatography of tissue lipidomes with the ERRα ligand-binding domain (LBD) and subsequent transcriptional assays identified cholesterol as an endogenous ERRα agonist. Perturbation of cholesterol biosynthesis or inhibition of ERRα revealed the interdependence of cholesterol and ERRα. In bone, the effects of cholesterol, statin, and bisphosphonate on osteoclastogenesis require ERRα; and consequently, cholesterol-induced bone loss or bisphosphonate osteoprotection is lost in ERRα knockout mice. Furthermore, statin induction of muscle toxicity and cholesterol suppression of macrophage cytokine secretion are impaired by loss or inhibition of ERRα. These findings reveal a key step in ERRα regulation and explain the actions of two highly prescribed drugs, statins and bisphosphonates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Bone Resorption
  • Cell Differentiation
  • Cell Line
  • Cholesterol / physiology*
  • Diphosphonates / pharmacology*
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Ligands
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Osteoclasts / drug effects
  • Osteoclasts / physiology
  • Protein Binding
  • Protein Domains
  • Receptors, Estrogen / physiology*
  • Simvastatin / pharmacology*


  • Diphosphonates
  • ERRalpha estrogen-related receptor
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Ligands
  • Receptors, Estrogen
  • Cholesterol
  • Simvastatin