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钙和镉对雌激素相关受体γ的激活作用。

Activation of estrogen-related receptor γ by calcium and cadmium.

机构信息

Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, United States.

Oncology, Georgetown University, Washington DC, United States.

出版信息

Front Endocrinol (Lausanne). 2024 Oct 23;15:1400022. doi: 10.3389/fendo.2024.1400022. eCollection 2024.

DOI:10.3389/fendo.2024.1400022
PMID:39507056
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11537906/
Abstract

OBJECTIVE

Estrogen-related receptor γ (ERRγ) is a metabolic regulator with no identified physiological ligands. This study investigates whether calcium is an ERRγ ligand that mediates the effects of glucagon and whether cadmium, which mimics the effects of calcium, disrupts metabolism through ERRγ.

METHOD

HepG2, MCF-7, and HEK293T transfected with ERRγ were treated with glucagon, calcium, cadmium, ERRγ agonist, or ERRγ inhibitor. Cells were then collected for assays including real-time qPCR, Western blot, ChIP, immunofluorescence, mutational analysis, or gene set enrichment analysis. Molecular dynamics simulations were performed to study mutation sites.

RESULTS

In HepG2 cells, treatment with glucagon, calcium, or cadmium re-localized ERRγ to the cell nucleus, recruited ERRγ to estrogen-related response elements, induced the expression of ERRγ-regulated genes, and increased extracellular glucose that was blocked by an ERRγ antagonist. In MCF-7 cells and HEK293T cells transfected with ERRγ, similar treatments induced the expression of metabolic genes. Mutational analysis identified S303, T429, and E452 in the ligand-binding domain as potential interaction sites. Molecular dynamics simulations showed that calcium induced changes in ERRγ similar to ERRγ agonist.

CONCLUSION

The results suggest that calcium is a potential ligand of ERRγ that mediates the effects of glucagon and cadmium disrupts metabolism through ERRγ.

摘要

目的

雌激素相关受体 γ（ERRγ）是一种代谢调节剂，目前尚未发现其生理配体。本研究旨在探讨钙是否为 ERRγ 的配体，介导胰高血糖素的作用，以及类似钙作用的镉是否通过 ERRγ 破坏代谢。

方法

用 ERRγ 转染 HepG2、MCF-7 和 HEK293T 细胞，用胰高血糖素、钙、镉、ERRγ 激动剂或 ERRγ 抑制剂处理细胞。然后收集细胞进行实时 qPCR、Western blot、ChIP、免疫荧光、突变分析或基因集富集分析。进行分子动力学模拟研究突变位点。

结果

在 HepG2 细胞中，胰高血糖素、钙或镉处理使 ERRγ重新定位到细胞核，募集 ERRγ 到雌激素相关反应元件，诱导 ERRγ 调节基因的表达，并增加细胞外葡萄糖，ERRγ 拮抗剂可阻断该作用。在转染 ERRγ 的 MCF-7 细胞和 HEK293T 细胞中，类似处理诱导代谢基因的表达。突变分析确定配体结合域中的 S303、T429 和 E452 为潜在的相互作用位点。分子动力学模拟表明钙诱导 ERRγ 发生类似于 ERRγ 激动剂的变化。

结论

结果表明，钙可能是 ERRγ 的配体，介导胰高血糖素的作用，而镉通过 ERRγ 破坏代谢。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/fc0ce9f46ea3/fendo-15-1400022-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/63adbdcae0c8/fendo-15-1400022-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/3333a2771bce/fendo-15-1400022-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/2e29941503e0/fendo-15-1400022-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/b39b2021bd9f/fendo-15-1400022-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/44754a726203/fendo-15-1400022-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/bd34172105fe/fendo-15-1400022-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/fc0ce9f46ea3/fendo-15-1400022-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/63adbdcae0c8/fendo-15-1400022-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/3333a2771bce/fendo-15-1400022-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/2e29941503e0/fendo-15-1400022-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/b39b2021bd9f/fendo-15-1400022-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/44754a726203/fendo-15-1400022-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/bd34172105fe/fendo-15-1400022-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/42d2/11537906/fc0ce9f46ea3/fendo-15-1400022-g007.jpg

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本文引用的文献

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