Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis
Abstract 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 wit...
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-03-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44320-024-00024-x |
| _version_ | 1797219495889076224 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Christian Sommerauer |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T12:34:34Z |
| format | Article |
| id | doaj.art-ee239cfd60044f218b6abfe27eac0000 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-04-24T12:34:34Z |
| publishDate | 2024-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-ee239cfd60044f218b6abfe27eac00002024-04-07T11:35:07ZengSpringer NatureMolecular Systems Biology1744-42922024-03-0120437440210.1038/s44320-024-00024-xEstrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosisChristian Sommerauer0Carlos J Gallardo-Dodd1Christina Savva2Linnea Hases3Madeleine Birgersson4Rajitha Indukuri5Joanne X Shen6Pablo Carravilla7Keyi Geng8Jonas Nørskov Søndergaard9Clàudia Ferrer-Aumatell10Grégoire Mercier11Erdinc Sezgin12Marion Korach-André13Carl Petersson14Hannes Hagström15Volker M Lauschke16Amena Archer17Cecilia Williams18Claudia Kutter19Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Medicine, Integrated Cardio Metabolic Center, Karolinska InstituteDepartment of Protein Science, KTH Royal Institute of Technology, Science for Life LaboratoryDepartment of Protein Science, KTH Royal Institute of Technology, Science for Life LaboratoryDepartment of Protein Science, KTH Royal Institute of Technology, Science for Life LaboratoryDepartment of Physiology and Pharmacology, Karolinska InstituteDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryDepartment of Physiology and Pharmacology, Karolinska InstituteDepartment of Women’s and Children’s Health, Karolinska Institute, Science for Life LaboratoryDepartment of Medicine, Integrated Cardio Metabolic Center, Karolinska InstituteDepartment of Drug Metabolism and Pharmacokinetics, The Healthcare Business of Merck KGaADepartment of Medicine Huddinge, Karolinska InstituteDepartment of Physiology and Pharmacology, Karolinska InstituteDepartment of Protein Science, KTH Royal Institute of Technology, Science for Life LaboratoryDepartment of Protein Science, KTH Royal Institute of Technology, Science for Life LaboratoryDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life LaboratoryAbstract 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.https://doi.org/10.1038/s44320-024-00024-xMASLDEstrogen ReceptorMulti-omicsEnhancer–Promoter InteractionTEAD1 |
| spellingShingle | 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 Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis Molecular Systems Biology MASLD Estrogen Receptor Multi-omics Enhancer–Promoter Interaction TEAD1 |
| title | Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis |
| title_full | Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis |
| title_fullStr | Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis |
| title_full_unstemmed | Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis |
| title_short | Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis |
| title_sort | estrogen receptor activation remodels tead1 gene expression to alleviate hepatic steatosis |
| topic | MASLD Estrogen Receptor Multi-omics Enhancer–Promoter Interaction TEAD1 |
| url | https://doi.org/10.1038/s44320-024-00024-x |
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