Identification of a Selective Inverse Agonist for the Orphan Nuclear Receptor Estrogen-Related Receptor α

Busch, Brett B.; Stevens, William C.; Martin, Richard; Ordentlich, Peter; Zhou, Sihong; Sapp, Douglas W.; Horlick, Robert A.; Mohan, Raju

doi:10.1021/jm049334f

Cited by 153 publications

(118 citation statements)

References 17 publications

(29 reference statements)

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“…Consistent with previous reports using genetic approaches (19,21), ERRα deficiency and treatment with XCT790 (29), an ERRα inhibitor, suppressed RANKL-induced osteoclast differentiation (Supplemental Figure 13 and Supplemental Figure 14A). Importantly, forced MYC expression, which restored osteoclast differentiation in MYC-deficient OCPs ( Figure 2D and Figure 5A, left panels), was not able to restore osteoclast differentiation when ERRα was inhibited by XCT790 ( Figure 5A).…”

Section: Resultssupporting

confidence: 92%

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae

Lee

Mun

et al. 2017

Journal of Clinical Investigation

112

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Section: Resultssupporting

confidence: 92%

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae

Lee

Mun

et al. 2017

Journal of Clinical Investigation

112

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“…As CD4 + T cells were also found to express PCG-1β (Fig. S3A), gene expression was analyzed by microarray in resting and stimulated ERRα −/− or WT CD4 + T cells after acute ERRα inhibition by the ERRα inverse agonist XCT790, which promotes acute ERRα degradation (25), or the chemically distinct ERRα antagonist compound A (18) (Fig. S3B).…”

Section: Resultsmentioning

confidence: 99%

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

196

189

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Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Tregbut not Teff-generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. glycolysis | fatty acid | oxidative metabolism | mammalian target of rapamycin | AMPK

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“…Although not regulated by natural ligands, ERR␣ can be deactivated by the synthetic molecule XCT790 (11,12). ERR␣ regulates fatty acid oxidation and the adaptive bioenergetic response (13,14).…”

mentioning

confidence: 99%

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes

Bonnelye¹,

Reboul²,

Duval³

et al. 2011

Arthritis & Rheumatism

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Objective. We reported previously that the orphan nuclear receptor, estrogen receptor-related receptor ␣ (ERR␣), is expressed in articular chondrocytes and is dysregulated in a mouse model of inflammatory arthritis. The aim of this study, therefore, was to determine whether ERR␣ is also dysregulated in patients with osteoarthritis (OA).Methods. ERR␣ messenger RNA (mRNA) and protein were quantified in normal and OA cartilage samples and in OA chondrocytes in vitro, with and without short-term treatment with a variety of OAassociated factors and signaling pathway agonists and inhibitors.Results. ERR␣ expression was lower in OA than in normal articular cartilage. Interleukin-1␤ (IL-1␤) markedly up-regulated ERR␣ expression in OA chondrocytes in vitro, and agonist or inhibitor treatment indicated that the up-regulation was dependent on cyclooxygenase 2 (COX-2; NS398), prostaglandin E 2 , cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERR␣ inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERR␣ by IL-1␤, suggesting autoregulation of ERR␣ in the IL-1␤ pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1␤ versus IL-1␤ alone, and the down-regulation of MMP-13 mRNA and protein observed with XCT790 alone suggests that the up-regulation of MMP-13 by IL-1␤ is ERR␣-dependent.Conclusion. We report the first evidence that ERR␣ expression is regulated by IL-1␤ in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERR␣ target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERR␣ may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.Osteoarthritis (OA) is a chronic disease characterized by slowly progressive destruction of the articular cartilage, combined with changes in the synovium and subchondral bone (1). Various estimates suggest that more than 40% of 70-year-old people currently have the disease, ranking OA as the most common arthritic condition. The prevalence and the pain and disability associated with progression of the disease have led to intense interest in defining markers for OA as well as the mechanisms underlying the disease.The cellular component of cartilage is the chondrocyte, and adult articular chondrocytes, although considered quiescent in normal cartilage, can respond to mechanical injury and biologic stimuli such as cytokines and growth factors. Interleukin-1␤ (IL-1␤) is a wellknown proinflammatory cytokine that is implicated in

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Identification of a Selective Inverse Agonist for the Orphan Nuclear Receptor Estrogen-Related Receptor α

Cited by 153 publications

References 17 publications

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes

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Identification of a Selective Inverse Agonist for the Orphan Nuclear Receptor Estrogen-Related Receptor α

Cited by 153 publications

References 17 publications

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

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Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E₂– and cAMP‐dependent pathways in osteoarthritic chondrocytes