Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects

Wei Wei, Adam G. Schwaid, Xueqian Wang, Xunde Wang, Shili Chen, Qian Chu, Alan Saghatelian, Yihong Wan

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)479-491
Number of pages13
JournalCell Metabolism
Volume23
Issue number3
DOIs
StatePublished - Mar 8 2016

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Wei, W., Schwaid, A. G., Wang, X., Wang, X., Chen, S., Chu, Q., Saghatelian, A., & Wan, Y. (2016). Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects. Cell Metabolism, 23(3), 479-491. https://doi.org/10.1016/j.cmet.2015.12.010