Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.
Christian SommerauerCarlos J Gallardo-DoddChristina SavvaLinnea HasesMadeleine BirgerssonRajitha IndukuriJoanne X ShenPablo CarravillaKeyi GengJonas Nørskov SøndergaardClàudia Ferrer-AumatellGrégoire MercierErdinc SezginMarion Korach-AndréCarl PeterssonHannes HagströmVolker Martin LauschkeAmena ArcherCecilia WilliamsClaudia KutterPublished in: Molecular systems biology (2024)
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.
Keyphrases
- estrogen receptor
- high fat diet
- insulin resistance
- end stage renal disease
- transcription factor
- gene expression
- small molecule
- high fat diet induced
- adipose tissue
- chronic kidney disease
- newly diagnosed
- ejection fraction
- peritoneal dialysis
- prognostic factors
- metabolic syndrome
- high glucose
- endothelial cells
- poor prognosis
- cell proliferation
- fatty acid
- drug induced
- oxidative stress
- electronic health record
- weight loss
- liver injury
- big data
- diabetic rats
- genome wide
- physical activity
- single molecule
- skeletal muscle
- body mass index
- single cell
- long non coding rna
- protein protein