Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand

Willy, Patricia J.; Murray, Ian R.; Qian, Jing; Busch, Brett B.; Stevens, William C.; Martin, Richard; Mohan, Raju; Zhou, Sihong; Ordentlich, Peter; Wei, Ping; Sapp, Douglas W.; Horlick, Robert A.; Heyman, Richard A.; Schulman, Ira G.

doi:10.1073/pnas.0401420101

Cited by 180 publications

(160 citation statements)

References 40 publications

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“…These receptors all share an extended half-site motif TCAAGGTCA and can bind as monomers, dimers or heterodimers ). Because these receptors have very small ligand biding pockets, endogenous ligand discovery remains unlikely, although synthetic ligands have been developed and ERRα is blocked by diethylstilbestrol, while ERRβ and γ are blocked by tamoxifen (Coward et al 2001;Greschik et al 2002;Willy et al 2004). The activity of ERRs appears to be constitutive, with the ligand binding pocket stably arranged in an active conformation without ligand (Xie et al 1999;Greschik et al 2002;Greschik et al 2004).…”

Section: Errsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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Section: Errsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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“…Although ERRα is an orphan nuclear receptor with no known endogenous ligand, the drug XCT790 acts as an inverse agonist to counteract the constitutive activity of ERRα (31). To complement the analysis using shRNA knockdown of ERRα, the effect of XCT790 on ADwt production was investigated.…”

Section: Pharmacological Inhibition Of Errα Is Detrimental To Hcmv Rementioning

confidence: 99%

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Hwang¹,

Purdy

Wu³

et al. 2014

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

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An shRNA-mediated screen of the 48 human nuclear receptor genes identified multiple candidates likely to influence the production of human cytomegalovirus in cultured human fibroblasts, including the estrogen-related receptor α (ERRα), an orphan nuclear receptor. The 50-kDa receptor and a 76-kDa variant were induced posttranscriptionally following infection. Genetic and pharmacological suppression of the receptor reduced viral RNA, protein, and DNA accumulation, as well as the yield of infectious progeny. In addition, RNAs encoding multiple metabolic enzymes, including enzymes sponsoring glycolysis (enolase 1, triosephosphate isomerase 1, and hexokinase 2), were reduced when the function of ERRα was inhibited in infected cells. Consistent with the effect on RNAs, a substantial number of metabolites, which are normally induced by infection, were either not increased or were increased to a reduced extent in the absence of normal ERRα activity. We conclude that ERRα is needed for the efficient production of cytomegalovirus progeny, and we propose that the nuclear receptor contributes importantly to the induction of a metabolic environment that supports optimal cytomegalovirus replication.herpesvirus | metabolism | nuclear receptor | mass spectrometry H uman cytomegalovirus (HCMV) belongs to the β-herpesvirus subfamily, and although most healthy individuals remain asymptomatic subsequent to infection, the pathogen is a major contributor to birth defects and to life-threatening disease in immunocompromised patients (1-3). As with all viruses, HCMV depends on the host cell to provide macromolecular building blocks for virion production, and throughout the course of its evolution, HCMV has adapted to manipulate numerous fundamental cellular processes, including RNA accumulation (4), translation (5), metabolism (6, 7), secretory pathways (8), and the cell cycle (9).The nuclear receptor gene family, of which there are 48 members in the human genome, encodes transcription factors (10). Some bind to specific hydrophobic ligands such as steroids, vitamin D, fatty acids, and lipids, providing a means to sense changes in the extracellular or intracellular environment; others are "orphans" with no known ligand, and are often constitutively active (11). As transcription factors that modulate broad gene regulatory networks, nuclear receptors control numerous physiological processes, including aspects of metabolism (cell autonomously and at the whole-organism level), development, and cellular differentiation, cancer, circadian rhythm, and immunity (11).The first indication that nuclear receptor signaling modulates HCMV replication surfaced after the identification of a retinoic acid response element within the major immediate-early promoter (MIEP) that caused a dose-dependent response to retinoic acid in reporter assays (12). Retinoic acid was further shown to enhance viral DNA replication and progeny production in human embryonal carcinoma cells and foreskin fibroblasts (13,14). The ligand also exacerbated symptoms of infection,...

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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).…”

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“…BONNELYE ET AL tween ERR␣ and the transcriptional coactivator, peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) (12). PGC-1␣ exhibits differential expression during chondrocyte differentiation and modulates SOX9 activity (26).…”

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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Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand

Cited by 180 publications

References 40 publications

Nuclear receptors, mitochondria and lipid metabolism

Nuclear receptors, mitochondria and lipid metabolism

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

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

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Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand

Cited by 180 publications

References 40 publications

Nuclear receptors, mitochondria and lipid metabolism

Nuclear receptors, mitochondria and lipid metabolism

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

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