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Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Sommerauer, Christian  ORCID logo  https://orcid.org/0000-0001-7132-7172
Gallardo-Dodd, Carlos J 
Savva, Christina 
Hases, Linnea 
Birgersson, Madeleine 

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.

Description

Keywords

Enhancer–Promoter Interaction, Estrogen Receptor, MASLD, Multi-omics, TEAD1, Animals, Female, Humans, Male, Mice, Diet, High-Fat, Estrogens, Fatty Liver, Gene Expression, Liver, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Receptors, Estrogen, TEA Domain Transcription Factors

Journal Title

Mol Syst Biol

Conference Name

Journal ISSN

1744-4292
1744-4292

Volume Title

20

Publisher

Springer Science and Business Media LLC
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