@article{275d38307f4749d2921863f343019a62,
title = "Ligand activation of ERRα 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 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.",
author = "Wei Wei and Schwaid, {Adam G.} and Xueqian Wang and Xunde Wang and Shili Chen and Qian Chu and Alan Saghatelian and Yihong Wan",
note = "Funding Information: We thank Russell DeBose-Boyd and Marc Schumacher (UT Southwestern) for reagents and advice on cholesterol depletion; David Mangelsdorf (UT Southwestern) for ERRα and PGC1α plasmids; Vincent Gigu{\`e}re (McGill University) for ERRαKO mice; and David Mangelsdorf, David Russell, Joseph Goldstein, Michael Brown, and Russell DeBose-Boyd for critical reading of the manuscript and constructive suggestions. This work was in part supported by the UT Southwestern Endowed Scholar Startup Fund (Y.W.), NIH (RO1DK089113, Y.W.), The Welch Foundation (I-1751, Y.W.), Mary Kay Foundation (#073.14, Y.W.), CPRIT (RP130145, Y.W.), Searle Foundation (08-SSP-108, A.S.), NCI Cancer Center Support Grant P30 (CA014195 MASS core, A.S.), The Leona M. and Harry B. Helmsley Charitable Trust grant (#2012-PG-MED002, A.S.), and Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals (A.S.). Funding Information: We thank Russell DeBose-Boyd and Marc Schumacher (UT Southwestern) for reagents and advice on cholesterol depletion; David Mangelsdorf (UT Southwestern) for ERRa and PGC1a plasmids; Vincent Gigu{\`e} re (McGill University) for ERRaKO mice; and David Mangelsdorf, David Russell, Joseph Goldstein, Michael Brown, and Russell DeBose-Boyd for critical reading of the manuscript and constructive suggestions. This work was in part supported by the UT Southwestern Endowed Scholar Startup Fund (Y.W.), NIH (RO1DK089113, Y.W.), The Welch Foundation (I-1751, Y.W.), Mary Kay Foundation (#073.14, Y.W.), CPRIT (RP130145, Y.W.), Searle Foundation (08-SSP- 108, A.S.), NCI Cancer Center Support Grant P30 (CA014195 MASS core, A.S.), The Leona M. and Harry B. Helmsley Charitable Trust grant (#2012- PG-MED002, A.S.), and Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals (A.S.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = mar,
day = "8",
doi = "10.1016/j.cmet.2015.12.010",
language = "English (US)",
volume = "23",
pages = "479--491",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}