Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis

Kim, Don-Kyu; Jeong, Jae-Ho; Lee, Ji-Min; Kim, Kwang S.; Park, Seung-Hwan; Kim, Yong Deuk; Koh, Minseob; Shin, Minsang; Jung, Yoon Seok; Kim, Hyung-Seok; Lee, Tae‐Hoon; Oh, Baek-Rock; Kim, Jae Il; Park, Hwan Tae; Jeong, Won–Il; Lee, Chul‐Ho; Park, Seung Bum; Min, Jung‐Joon; Jung, Seung Pil; Choi, Seok‐Yong; Choy, Hyon E.; Choi, Hueng‐Sik

doi:10.1038/nm.3483

Cited by 128 publications

(140 citation statements)

References 24 publications

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“…Like many other nuclear receptors, the activities of ERR␣ and ERR␥ can be modulated by available small-molecule ligands (C29, XCT790, GSK5182, GSK4716, etc.) (68)(69)(70)(71). Future efforts to test ERR␣ and ERR␥ ligands in animal models or even clinical settings of cardiac disease will help uncover their therapeutic values.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Wang

McDonald

Petrenko

et al. 2015

Molecular and Cellular Biology

111

108

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f Almost all cellular functions are powered by a continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors estrogen-related receptor ␣ (ERR␣) and ERR␥ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERR␣ and ERR␥ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERR␣ and ERR␥ influence major cardiomyocyte energy consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis, and conduction genes. Mice lacking both ERR␣ and cardiac ERR␥ develop severe bradycardia, lethal cardiomyopathy, and heart failure featuring metabolic, contractile, and conduction dysfunctions. These results illustrate that the ERR transcriptional pathway is essential to couple cellular energy metabolism with energy consumption processes in order to maintain normal cardiac function. E very cell's own survival and vital functions are supported by energy-generating metabolic pathways. The cellular energy supply and demand must be coordinated, and an imbalance results in cellular dysfunctions and diseases from heart failure to obesity (1, 2). Although the regulation of cellular energy production and consumption individually are focuses of intensive research, it is little understood how these two processes are coordinated. One possible mechanism lies at the level of transcription where the expression of genes critical in both cellular energy production and utilization processes can be regulated in an orchestrated manner. However, such transcription coordinators that directly regulate multiple energy-generating cellular metabolic pathways and energy-consuming cellular functions remain to be established.The heart offers an ideal system for studying coordination of energy production and consumption. It continuously pumps blood to all the organs, involving energy-demanding processes such as myocardial contraction and electrical conduction (3). Accordingly, cardiomyocytes maintain an exceedingly high metabolic rate and depend on vigorous fatty acid oxidation (FAO), oxidative phosphorylation (OxPhos), and dynamic mitochondrial networks to generate energy that supports these functions (4, 5). Indeed, defects in cardiomyocyte metabolism and mitochondrial function are underlying causes of, or are associated with, many cardiac diseases, including cardiomyopathy and heart failure, that affect millions of people (6-9).Nuclear receptors (NRs) are ligand-activated transcription factors with important roles in both physiological and pathological settings (10-12). Among the 48 NRs in the human genome, several NRs and their coactivators have been identified as key regulators of cardiac metabolism (13-16). In particular, recent work has revealed...

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Section: Discussionmentioning

confidence: 99%

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Wang

McDonald

Petrenko

et al. 2015

Molecular and Cellular Biology

111

108

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“…The ERR isoforms are primarily expressed in several organs, such as the heart, brain, kidney, pancreas, and liver (16,17). Recently, studies have shown that ERRg is involved in metabolic diseases such as type 2 diabetes mellitus, alcohol-induced oxidative stress, liver injury, and microbial infection through impaired hepatic gluconeogenesis (18,19), hepatic insulin signaling (20), and iron metabolism (21).…”

mentioning

confidence: 99%

Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells

et al. 2015

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Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ. Methods: Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of 131 I was determined by clonogenic assay. Results: Treatment with GSK5182 resulted in doseand time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of 131 I treatment in ATC cells. Conclusion: These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.

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“…They are primarily expressed in tissues such as the heart, brain, kidney, pancreas, placenta, and liver [2], and are known to play a pivotal role in the development of diseases such as cancer and various metabolic disorders [3]. Among the ERRs, ERRγ in particular has been shown to be involved in metabolic diseases such as type 2 diabetes mellitus, alcohol-induced oxidative stress, liver injury, and microbial infections caused by impaired hepatic gluconeogenesis [4,5], impaired hepatic insulin signaling [6], and impaired iron metabolism [7].…”

Section: Introductionmentioning

confidence: 99%

“…Several lines of evidence have revealed that the ERRγ inverse agonist 4 alleviates diabetes through the inhibition of hepatic gluconeogenesis in a PGC-1α-dependent manner [5]. Additionally, 4 has antimicrobial effects by reducing ERRγ-mediated hepcidin mRNA expression [7]. More recently, it was reported that 4 enhances the responsiveness of radioiodine therapy by modulating sodium iodide symporter (NIS) function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway [12].…”

Section: Introductionmentioning

confidence: 99%

Identification of Selective ERRγ Inverse Agonists

Kim

Yoo

et al. 2016

Molecules

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GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC 50 = 0.44, >10, >10, and 10 µM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 µM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

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Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis

Cited by 128 publications

References 24 publications

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells

Identification of Selective ERRγ Inverse Agonists

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