肝雌激素相关受体γ是急性和慢性肝损伤中GDF15产生的关键调节因子。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology Pub Date : 2025-05-14 DOI:10.1016/j.mce.2025.112572

Yoon Seok Jung , Kamalakannan Radhakrishnan , Jung-Ran Noh , Yong-Hoon Kim , Chul-Ho Lee , Hueng-Sik Choi

{"title":"肝雌激素相关受体γ是急性和慢性肝损伤中GDF15产生的关键调节因子。","authors":"Yoon Seok Jung , Kamalakannan Radhakrishnan , Jung-Ran Noh , Yong-Hoon Kim , Chul-Ho Lee , Hueng-Sik Choi","doi":"10.1016/j.mce.2025.112572","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.</div></div><div><h3>Materials and methods</h3><div>Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl<sub>4</sub>) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.</div></div><div><h3>Key findings</h3><div>Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.</div></div><div><h3>Significance</h3><div>Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112572"},"PeriodicalIF":3.8000,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hepatic estrogen-related receptor gamma is a key regulator of GDF15 production in acute and chronic liver injury\",\"authors\":\"Yoon Seok Jung , Kamalakannan Radhakrishnan , Jung-Ran Noh , Yong-Hoon Kim , Chul-Ho Lee , Hueng-Sik Choi\",\"doi\":\"10.1016/j.mce.2025.112572\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><div>Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.</div></div><div><h3>Materials and methods</h3><div>Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl<sub>4</sub>) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.</div></div><div><h3>Key findings</h3><div>Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.</div></div><div><h3>Significance</h3><div>Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.</div></div>\",\"PeriodicalId\":18707,\"journal\":{\"name\":\"Molecular and Cellular Endocrinology\",\"volume\":\"606 \",\"pages\":\"Article 112572\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-05-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and Cellular Endocrinology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0303720725001236\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0303720725001236","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

目的：生长分化因子15 （GDF15）是一种应激诱导的肝因子，在肝损伤中起着新的作用。雌激素相关受体γ (ERRγ)是一种调节线粒体功能和代谢应激的核受体，也与各种肝损伤有关。然而，ERRγ和GDF15之间的调控相互作用尚不清楚。本研究探讨了GDF15在肝脏中表达和分泌的分子机制，重点研究了ERRγ在急性和慢性肝损伤中的作用。材料和方法：野生型和肝细胞特异性ERRγ敲除（ERRγ- lko）小鼠分别给予单剂量四氯化碳（CCl4）或含酒精饮食4周，建立急性或慢性肝损伤模型。ERRγ通过腺病毒构建体（Ad-ERRγ）过表达。ERRγ特异性逆激动剂GSK5182抑制ERRγ的转激活。荧光素酶报告基因检测用于评估ERRγ蛋白与GDF15基因调控区域的结合。关键发现：急性和慢性肝损伤患者肝脏ERRγ和GDF15基因表达及GDF15蛋白切片均显著升高。腺病毒介导的ERRγ过表达足以显著增加肝脏GDF15的表达和分泌。在急性和慢性肝损伤中，ERRγ表达的基因消融或ERRγ反激活的药理抑制实质上抑制了肝脏GDF15表达和产生的上调。此外，报告基因分析表明，ERRγ而不是ERRα或ERRβ直接结合并激活GDF15基因启动子。意义：我们的研究结果强调了ERRγ在GDF15基因表达和产生的转录调控中对肝损伤的重要作用。了解GDF15表达的调控机制可能会导致新的治疗靶点，以保护肝脏免受各种类型的损伤和相关疾病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Hepatic estrogen-related receptor gamma is a key regulator of GDF15 production in acute and chronic liver injury

Aims

Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.

Materials and methods

Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl₄) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.

Key findings

Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.

Significance

Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Molecular and Cellular Endocrinology 医学-内分泌学与代谢

CiteScore

9.00

自引率

2.40%

发文量

174

审稿时长

42 days

期刊介绍： Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.