The Nuclear Receptor ERRα Is Required for the Bioenergetic and Functional Adaptation to Cardiac Pressure Overload

Huss, Janice M.; Imahashi, Kenichi; Dufour, Catherine R.; Weinheimer, Carla J.; Courtois, Michael; Kovács, Atilla; Giguère, Vincent; Murphy, Elizabeth; Kelly, Daniel P.

doi:10.1016/j.cmet.2007.06.005

Cited by 236 publications

(220 citation statements)

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“…What occurs may represent a skewed stoichiometric ratio of target genes. As a consequence, levels of key enzymes and signaling molecules may exceed homeostatic safety margins where mild physiologic challenges or developmental transitions produce decompensation Huss et al 2007). Much remains to be learned about the actions of nuclear receptors from conditional loss of receptors by genetic methods as well as combinatorial uses of ligands to 'dial-in' metabolic treatments (Lalloyer et al 2006;Schug et al 2007).…”

Section: Resultsmentioning

confidence: 99%

“…(Puigserver et al 1998;Herzig et al 2001;Lin et al 2002;Puigserver et al 2003;Rhee et al 2003;Arany et al 2005;St-Pierre et al 2006;Handschin et al 2007). While named for its interaction with PPARγ, many of these PGC-1-dependent adaptations appear to be largely dependent on ERRs and other metabolic transcription factors that are independent of PPAR/RXR Rhee et al 2003;Schilling et al 2006;Alaynick et al 2007;Huss et al 2007;Villena et al 2007). …”

Section: Pgc-1αmentioning

confidence: 99%

“…In the mouse intestine, ERRα controls the ApoA-IV promoter and loss results in reduced uptake of lipids (Luo et al 2003;Carrier et al 2004). At the cellular level, defects in oxidative metabolism have been seen in ERRα null intestine, skeletal muscle, heart, and BAT (Carrier et al 2004;Rodriguez-Calvo et al 2006;Huss et al 2007;Villena et al 2007). Several target genes have been identified by these studies including Ckmt2, Mcad, Sdha and Sdhb ).…”

Section: Errαmentioning

confidence: 99%

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Nuclear receptors, mitochondria and lipid metabolism

Alaynick

2008

Mitochondrion

126

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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: Resultsmentioning

confidence: 99%

Section: Pgc-1αmentioning

confidence: 99%

Section: Errαmentioning

confidence: 99%

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Nuclear receptors, mitochondria and lipid metabolism

Alaynick

2008

Mitochondrion

126

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“…7). Hexokinase 2 (HK2) and adenine nucleotide translocase 1 (ANT1) were among the hits, and both are known to be regulated by ERRα (36,56,57). Both enzymes support core metabolism: HK2 phosphorylates glucose (58) and ANT1 exchanges mitochondrial ATP for cytosolic ADP (59).…”

Section: Discussionmentioning

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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“…ERR␣ regulates fatty acid oxidation and the adaptive bioenergetic response (13,14). ERR␣ is highly expressed in skeletal (bone and cartilage) tissues (15,16) and has been reported to regulate osteoblast development and bone formation both in vitro (15,16) and in vivo (17,18).…”

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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The Nuclear Receptor ERRα Is Required for the Bioenergetic and Functional Adaptation to Cardiac Pressure Overload

Cited by 236 publications

References 54 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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The Nuclear Receptor ERRα Is Required for the Bioenergetic and Functional Adaptation to Cardiac Pressure Overload

Cited by 236 publications

References 54 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

Contact Info

Product

Resources

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