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Ligand Activation of ERR? by Cholesterol Mediates Statin and Bisphosphonate Effects.


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 ? (ERR?). ERR? has important roles in cancer, metabolism, and skeletal homeostasis. Affinity chromatography of tissue lipidomes with the ERR? ligand-binding domain (LBD) and subsequent transcriptional assays identified cholesterol as an endogenous ERR? agonist. Perturbation of cholesterol biosynthesis or inhibition of ERR? revealed the interdependence of cholesterol and ERR?. In bone, the effects of cholesterol, statin, and bisphosphonate on osteoclastogenesis require ERR?; and consequently, cholesterol-induced bone loss or bisphosphonate osteoprotection is lost in ERR? knockout mice. Furthermore, statin induction of muscle toxicity and cholesterol suppression of macrophage cytokine secretion are impaired by loss or inhibition of ERR?. These findings reveal a key step in ERR? regulation and explain the actions of two highly prescribed drugs, statins and bisphosphonates.

SUBMITTER: Wei W 

PROVIDER: S-EPMC4785078 | BioStudies | 2016-01-01

REPOSITORIES: biostudies

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