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

43 Citations (Scopus)

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

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Diphosphonates
Estrogen Receptors
Cholesterol
Ligands
Cytoplasmic and Nuclear Receptors
Bone and Bones
Regulator Genes
Affinity Chromatography
Osteogenesis
Knockout Mice
Estrogens
Homeostasis
Macrophages
Cytokines
Gene Expression
Muscles

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects. / Wei, Wei; Schwaid, Adam G.; Wang, Xueqian; Wang, Xunde; Chen, Shili; Chu, Qian; Saghatelian, Alan; Wan, Yihong.

In: Cell Metabolism, Vol. 23, No. 3, 08.03.2016, p. 479-491.

Research output: Contribution to journalArticle

Wei, W, Schwaid, AG, 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, vol. 23, no. 3, pp. 479-491. https://doi.org/10.1016/j.cmet.2015.12.010
Wei, Wei ; Schwaid, Adam G. ; Wang, Xueqian ; Wang, Xunde ; Chen, Shili ; Chu, Qian ; Saghatelian, Alan ; Wan, Yihong. / Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects. In: Cell Metabolism. 2016 ; Vol. 23, No. 3. pp. 479-491.
@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",
year = "2016",
month = "3",
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",

}

TY - JOUR

T1 - Ligand activation of ERRα by cholesterol mediates statin and bisphosphonate effects

AU - Wei, Wei

AU - Schwaid, Adam G.

AU - Wang, Xueqian

AU - Wang, Xunde

AU - Chen, Shili

AU - Chu, Qian

AU - Saghatelian, Alan

AU - Wan, Yihong

PY - 2016/3/8

Y1 - 2016/3/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84960808488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960808488&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2015.12.010

DO - 10.1016/j.cmet.2015.12.010

M3 - Article

C2 - 26777690

AN - SCOPUS:84960808488

VL - 23

SP - 479

EP - 491

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 3

ER -