Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter
{"title":"雌激素受体激活可重塑 TEAD1 基因表达,从而缓解肝脏脂肪变性。","authors":"Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter","doi":"10.1038/s44320-024-00024-x","DOIUrl":null,"url":null,"abstract":"<p><p>Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":8.5000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987545/pdf/","citationCount":"0","resultStr":"{\"title\":\"Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.\",\"authors\":\"Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter\",\"doi\":\"10.1038/s44320-024-00024-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.</p>\",\"PeriodicalId\":18906,\"journal\":{\"name\":\"Molecular Systems Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.5000,\"publicationDate\":\"2024-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987545/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Systems Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s44320-024-00024-x\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Systems Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44320-024-00024-x","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/8 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.
期刊介绍:
Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems.
Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.