Molecular and Cellular Endocrinology最新文献

{"title":"White beans (Phaseolus vulgaris L.) in diet reduces hypothalamic pro-inflammatory cytokines improving insulin resistance in small litter grown rats","authors":"Ester Vieira Alves ,&nbsp;Tatiane Vieira Alves ,&nbsp;Lauro Sergio Barrozo Junior ,&nbsp;Marcos Vinícius de Freitas Ribeiro ,&nbsp;Adriel Felipe Freitas Nunes ,&nbsp;Camila Luiza Rodrigues dos Santos Ricken ,&nbsp;Ingridys Regina Borkenhagen ,&nbsp;Bruno Vargas Teixeira Cavalheiro ,&nbsp;Ginislene Dias ,&nbsp;Ricardo de Oliveira ,&nbsp;Gisele Facholi Bomfim ,&nbsp;Júlio Cezar de Oliveira","doi":"10.1016/j.mce.2025.112587","DOIUrl":"10.1016/j.mce.2025.112587","url":null,"abstract":"<div><div>In the present study we were interested in studying the effect of white beans (<em>Phaseolus vulgaris</em> L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was adjusted to 3 pups on post-natal day 3, while normal litter (NL) was kept with 8 pups. The milk collection and milk intake were performed, and the rat-offspring when weaned (at 22 days old), were fed a standard (NL-SD and SL-SD groups) or a white bean (2.5 % w/w) supplemented diet (NL-WB and SL-WB groups). Body weight, food and water intake were measured from weaning until adulthood (100 days old). Glucose and insulin tolerance, and intracerebroventricular insulin (10⁻³ mmol/L) tests were performed to assess peripheral and central insulin-glucose homeostasis in adult rats. Blood, hypothalamus, visceral fat pad and lean mass were collected. Milk from SL mothers displays high content of glucose, cholesterol, triglycerides and energy (<em>P</em> &lt; 0.05). Milk consumption by SL rat-offspring, in early stage of suckling, was higher than NL rats (<em>P&lt;</em>0.05). At adulthood, SL-SD rats were obese, hyperphagic, dyslipidemic, hyperglycemic, glucose intolerant and IR (<em>P</em> &lt; 0.05). At adulthood, SL-SD rats displayed central IR and higher hypothalamic pro-inflammatory (TNF-α, 43.5 %; IL-6, 78.5 % and IL-1β, 50.1 %, <em>P</em> &lt; 0.05) cytokine. The habitual ingestion of white beans-dietary supplementation prevented all those metabolic disruptions. In summary, white beans-dietary supplementation prevented obesity and glucose-insulin homeostasis deregulation in early overfeeding rats, avoiding hypothalamic inflammatory cytokines high levels and improving insulin sensitivity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112587"},"PeriodicalIF":3.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease-associated SNP variants of THRβ: Insights into the molecular determinants of aberrant receptor function","authors":"Ghausiya Rehman ,&nbsp;Amit Kumar Srivastav ,&nbsp;Sheeba Rizvi ,&nbsp;Ayushi Chhabra ,&nbsp;Rakesh K. Tyagi","doi":"10.1016/j.mce.2025.112585","DOIUrl":"10.1016/j.mce.2025.112585","url":null,"abstract":"<div><div>Thyroid hormone receptor beta (THRβ) is a ligand-modulated transcription factor that regulates thyroid hormone (T₃)-mediated genomic actions. It regulates the hypothalamus-pituitary-thyroid axis and various metabolic processes, primarily in the liver and kidney. Research has shown that genetic variations, mainly single nucleotide polymorphism (SNP) in the <em>THRB</em> gene, may be linked to diseases like resistance to thyroid hormone, thyroid-related cancers, neurological and mental disorders. Despite this revelation, a significant gap remains in understanding the impact of SNPs on THRβ cellular function and disease etiology. Thus, the present study investigated the disease-associated missense THRβ-SNPs using both <em>in silico</em> analysis and cell-based assays. The study was initiated with computational analysis of disease-associated THRβ variants to predict the effects of SNPs on receptor conformation, structure, stability, and function. The molecular docking and simulation approach then evaluated the impact of these variants on interactions with T₃ and RXR. Following this, an extensive investigation was conducted into the dynamics and functioning of these receptor variants to address the underlying deviations in their cellular functioning by assessing receptor-subcellular localization, response to T₃ hormone, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions encountered in healthy and disease states. The study emphasizes that the structural and conformational integrity of THRβ is essential for its normal function, and critical deviations are associated with several metabolic/endocrine disease states. A comprehensive analysis of these disease-associated THRβ variants suggests the prospects of personalized medicine and the development of SNP-based genomic tests. The findings may also facilitate the discovery of novel small-molecule modulators to treat thyroid-related diseases linked to THRβ dysfunction, improving diagnosis and management of disease conditions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112585"},"PeriodicalIF":3.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The lysosome-associated SLAMF7 inhibits the development of ovarian cancer by promoting lysosomal damage","authors":"Wen Zou ,&nbsp;Xiaoling Fang ,&nbsp;Zou Qian ,&nbsp;Lan Nie","doi":"10.1016/j.mce.2025.112586","DOIUrl":"10.1016/j.mce.2025.112586","url":null,"abstract":"<div><div>Ovarian cancer (OC) is one of the most severe cancers worldwide. Recent research suggests that the lysosomal pathway could be applied for early disease screening, prognosis evaluation, and adjuvant therapy. However, whether lysosome-related genes were applied for immune and prognosis prediction in OC remains unclear. RNA sequencing datasets, including clinical information of OC patients, were collected from TCGA and GEO databases. Lysosome-related prognostic genes and functional pathways in OC were identified using the lysosome dataset. The prognostic value of the most significant lysosome-related gene, SLAMF7, was estimated using Kaplan-Meier survival analysis. Differences in genomic mutations, tumor microenvironment immune infiltration, and drug resistance were evaluated in the high/low SLAMF7 of OC patients. The effect of SLAMF7 overexpression on the malignant characteristics of OC was assessed using OC cell lines (HEY A8 and OVCAR3 cells) and a xenograft mouse model. Based on the functional prediction of lysosome-related genes, T cell activation, immune receptor activity, and lysosomal pathways were significantly enriched in OC. Dimensionality reduction analysis using the random survival forest method confirmed that SLAMF7 was the most significantly different lysosome-related prognostic gene in OC. SLAMF7 was downregulated in OC cells and was associated with poor prognosis in OC patients. Low SLAMF7 expression was positively associated with chemotherapy sensitivity, immune infiltration, and function in OC patients. Overexpression of SLAMF7 promoted the pro-CTSB and LAMP1 expression, and inhibited CTSD expression in HEY A8 and OVCAR3 cells. Overexpression of SLAMF7 inhibited proliferation and formation of subcutaneous tumors in nude mice. The lysosome-related gene SLAMF7 is downregulated in OC and could serve as a prognostic biomarker. Overexpression of SLAMF7 inhibited the malignant of OC cells and tumor formation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112586"},"PeriodicalIF":3.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic characterization of the synergy between human induced pluripotent stem cells-derived liver- and pancreas-on-chip coculture","authors":"Amal Essaouiba ,&nbsp;Rachid Jellali ,&nbsp;Stéphane Poulain ,&nbsp;Soo Hyeon Kim ,&nbsp;Mathieu Danoy ,&nbsp;Cécile Legallais ,&nbsp;Yasuyuki Sakai ,&nbsp;Eric Leclerc","doi":"10.1016/j.mce.2025.112582","DOIUrl":"10.1016/j.mce.2025.112582","url":null,"abstract":"<div><div>Interactions between the liver and pancreas are key features of the carbohydrate and lipid homeostasis in healthy and pathological patients. To investigate the crosstalk between the two organs, we have developed an organ-on-chip coculture model derived from human induced pluripotent stem cells. The presence of pancreatic-derived tissue in the culture environment contributed to increase the CYP3A4 activity, the glycogen storage, and the expression of genes related to lipids, bile acids and sterol metabolism in the liver derived tissue. Concomitantly, the presence of liver cells led to increase the C-peptide secretion in pancreas. The coculture with liver modulated the pancreatic differentiation by increasing the activity of important transcription factors (REST, MAFB, PBX1) and by downregulating several hormone encoding genes (INS, GCG, TTR). The liver also stimulated the expression of genes involved in the response to inflammation in pancreas (<em>via</em> TGFβ/SMAD pathway). In parallel we observed a pancreatic cell reorganization coupled with the activation of the cell proliferation related transcription factor (SCRT1) and the upregulation of cellular remodeling genes (FLNA, FLNB, FN1, COL4A5). Finally, the pancreatic lipid genes were also upregulated in presence of the liver tissue. Overall, our results reflect a complex synergy between both tissues. We believe that those results are an encouraging step toward the development of relevant human model using advanced organ-on-chip technology and stem cells sources.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112582"},"PeriodicalIF":3.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydroepiandrosterone (DHEA)-induced autophagy protects against lipotoxicity in hepatic cells","authors":"Pratima Gupta,&nbsp;Archana Tewari,&nbsp;Sangam Rajak,&nbsp;Ambuj Shahi,&nbsp;Abhishek Yadav,&nbsp;Sana Raza,&nbsp;Rohit A. Sinha","doi":"10.1016/j.mce.2025.112584","DOIUrl":"10.1016/j.mce.2025.112584","url":null,"abstract":"<div><div>Dehydroepiandrosterone (DHEA), a precursor of sex hormones, has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), with studies suggesting a strong correlation between DHEA levels and disease severity. In this study, we demonstrated that DHEA alleviated lipotoxicity-induced hepatic damage by promoting autophagy.</div><div>Our findings demonstrate that DHEA-induced autophagy is mediated by estrogen receptor alpha (ER-α) and androgen receptor (AR) activation and protects hepatic cells against palmitate-induced apoptosis, steatosis, and inflammasome activation. DHEA treatment in a murine NASH model induced significant autophagy in the liver, further supporting the hepatoprotective role of DHEA. Collectively, our results identified DHEA as a pro-autophagic hormone with therapeutic potential for the treatment of lipotoxicity in NASH.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112584"},"PeriodicalIF":3.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen receptor plays critical role in regulating cervical cancer cell migration","authors":"Sarpita Bose ,&nbsp;Subhrangshu Das ,&nbsp;Sebabrata Maity ,&nbsp;Deblina Raychaudhuri ,&nbsp;Tania Banerjee ,&nbsp;Madhurima Paul ,&nbsp;Asima Mukhopadhyay ,&nbsp;Oishee Chakrabarti ,&nbsp;Saikat Chakrabarti","doi":"10.1016/j.mce.2025.112583","DOIUrl":"10.1016/j.mce.2025.112583","url":null,"abstract":"<div><div>Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify newer candidates for targeted therapy in metastatic disease. This study used a graph-theory-based network analysis to identify important interacting proteins (IIPs) with maximum connectivity, high centrality scores, and significant global and local network perturbation scores. Among the identified IIPs, the Androgen receptor (AR) emerged as one of the crucial yet understudied regulator in cervical cancer. Patient samples, ex vivo, and in vitro experiments showed significant downregulation of AR in cervical cancer. Ligand-dependent overexpression of AR reduced cancer cell migration while failed to induce apoptosis in CC cell lines. Downregulation of mesenchymal markers and restoration of epithelial markers upon exogenous expression of AR suggested its potential in reversing invasive properties of cervical cancer cells. AR overexpression followed by activation upregulated its downstream target PTEN and downregulated pPI3K levels, which in turn restored GSK3β activity by interfering with AKT phosphorylation, probably leading to degradation of mesenchymal markers in cervical cancer cells. Further studies showed that AR reduced cell motility by hindering focal adhesion formation and Actin filament assembly. An increased G-Actin ratio suggested AR disrupted cytoskeletal dynamics through altering the RhoA/ROCK1/LIMK1/CFL1 pathway eventually impeding cervical cancer cell spread.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112583"},"PeriodicalIF":3.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Açaí seed extract mitigates intestinal and hypothalamic alterations in obese mice","authors":"Bernardo Junqueira de Moraes Arnoso ,&nbsp;Caroline Alves de Araújo ,&nbsp;Giovana Dias Ramundo ,&nbsp;Graziele Freitas de Bem ,&nbsp;Dayane Teixeira Ognibene ,&nbsp;Fabricia Lima Fontes-Dantas ,&nbsp;Bruna Cadete Martins ,&nbsp;Julio Beltrame Daleprane ,&nbsp;Melina Oliveira de Souza ,&nbsp;Angela Castro Resende ,&nbsp;Cristiane Aguiar da Costa","doi":"10.1016/j.mce.2025.112574","DOIUrl":"10.1016/j.mce.2025.112574","url":null,"abstract":"<div><div>Obesity is a significant health concern, significantly contributing to increased morbidity and mortality by disrupting multiple physiological systems. It is strongly associated with metabolic dysfunctions, including impaired glycemic homeostasis, compromised intestinal barrier integrity, and gut microbiota imbalances, all exacerbating the risk of chronic diseases. The hydroalcoholic extract of açaí seeds (ASE), rich in phenolic compounds, has demonstrated beneficial effects on obesity and hyperglycemia; however, its impacts on gut health and gut-hypothalamus communication remain unclear. This study aimed to investigate the therapeutic effect of ASE in intestinal and hypothalamic alterations associated with obesity and compare it with Metformin. Male C57BL/6 mice were fed a high-fat or standard diet for 14 weeks. The ASE (300 mg/kg/day) and Metformin (300 mg/kg/day) treatments started in the tenth week until the fourteenth week, totaling four weeks of treatment. Our data show that the treatment with ASE and Metformin reduced body weight, ameliorated lipid profile, hyperglycemia, and plasma hyperleptinemia, and decreased the oxidative damage in the gut by reducing immunostaining of 8-isoprostane and NOX-4 expression, and improved the intestinal parameters and hypothalamic gene expression. Obesity-induced dysbiosis in the HF group was marked by reduced Proteobacteria and elevated LPS plasma levels, which were improved by treatments with ASE and Metformin. These findings suggest that ASE and Metformin are promising strategies to counteract the adverse effects of obesity on intestinal health and gut-hypothalamus communication, though they act through distinct mechanisms. Therefore, we can suggest that ASE is a promising natural product for treating the intestinal alterations associated with obesity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112574"},"PeriodicalIF":3.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryo-derived human chorionic gonadotropin promotes human decidualization through activating epithelial prostaglandin F2α secretion","authors":"Dan-Dan Jin ,&nbsp;Yu-Ying He ,&nbsp;Feng Ran ,&nbsp;Hong-Yuan Yang ,&nbsp;Gui-Jun Yan ,&nbsp;Zeng-Ming Yang","doi":"10.1016/j.mce.2025.112581","DOIUrl":"10.1016/j.mce.2025.112581","url":null,"abstract":"<div><div>Decidualization of endometrial stromal cells is important for pregnancy in rodents and humans. Dysfunction of decidualization can lead to implantation failure and recurrent miscarriage. Although the amount of PGF2α in uterine fluid increases during embryo implantation, what stimulates the production of PGF2α in the uterus and whether PGF2α is involved in embryo implantation and decidualization are still unknown. In our study, human chorionic gonadotropin (hCG), an embryo-derived protein, stimulates human endometrial epithelial cells to increase the levels of PGF2α synthesis-related enzymes (cPLA2, COX-1, COX-2, and AKR1C3) and to secrete PGF2α. Epithelial PGF2α induces EREG and HB-EGF secretion by activating ADAM17. The level of IGFBP1, a marker of human in vitro decidualization, is significantly increased by EREG or HB-EGF. PGF2α is also able to increase the IGFBP1 level in humans during in vitro decidualization. Our results indicate that hCG stimulates uterine epithelial PGF2α production to induce in vitro decidualization through EREG and HB-EGF.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112581"},"PeriodicalIF":3.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay between FOXO1 and glucocorticoid signaling in promoting the terminal differentiation of somatotropes","authors":"Pratyusa Das,&nbsp;Caitlin E. Stallings ,&nbsp;Ridwanullah A. Abubakar,&nbsp;Nooshin Mojahed,&nbsp;Shalini Guha,&nbsp;Dania Abou-Jabal,&nbsp;Buffy S. Ellsworth","doi":"10.1016/j.mce.2025.112573","DOIUrl":"10.1016/j.mce.2025.112573","url":null,"abstract":"<div><div>Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FOXO1, severely impairs glucocorticoid-induced expression of the gene encoding growth hormone (<em>Gh1</em>) both <em>in vitro</em> and <em>in vivo</em>. The mechanism appears to involve glucocorticoid induction of <em>Foxo1</em> expression, nuclear localization, and increased binding associated with the <em>Gh1</em> gene. An additional mechanism includes stabilization of the glucocorticoid receptor, NR3C1, possibly through FOXO1 induction of the chaperone protein, HSP90. Together these data suggest that glucocorticoid signaling and FOXO1 cooperate to promote <em>Gh1</em> expression, an essential aspect of somatotrope terminal differentiation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112573"},"PeriodicalIF":3.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic estrogen-related receptor gamma is a key regulator of GDF15 production in acute and chronic liver injury","authors":"Yoon Seok Jung ,&nbsp;Kamalakannan Radhakrishnan ,&nbsp;Jung-Ran Noh ,&nbsp;Yong-Hoon Kim ,&nbsp;Chul-Ho Lee ,&nbsp;Hueng-Sik Choi","doi":"10.1016/j.mce.2025.112572","DOIUrl":"10.1016/j.mce.2025.112572","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 (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.</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":3.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}