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

Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects.

Author information

1
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
3
Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: asaghatelian@salk.edu.
5
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yihong.wan@utsouthwestern.edu.

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.

PMID:
26777690
PMCID:
PMC4785078
DOI:
10.1016/j.cmet.2015.12.010
[Indexed for MEDLINE]
Free PMC Article

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