Abstract
AbstractSex-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.
Funder
Knut och Alice Wallenbergs Stiftelse
Ruth och Richard Julins Stiftelse
Science for Life Laboratory
Vetenskapsrådet
Karolinska Institutet
Robert Lundbergs Minnesstiftelse
EC | Erasmus+
Novo Nordisk Fonden
Lisa och Johan Grönbergs Stiftelse
AstraZeneca
Lillian Sagen & Curt Ericsson research foundation
Goesta Milton’s research foundation
Chinese Scholarship Council
National Microscopy Infrastructure, NMI
National Academic Infrastructure for Supercomputing in Sweden (NAISS) at UPPMAX
Publisher
Springer Science and Business Media LLC
Reference66 articles.
1. Ambrosini G, Groux R, Bucher P (2018) PWMScan: a fast tool for scanning entire genomes with a position-specific weight matrix. Bioinformatics 34:2483–2484
2. Ardestani A, Lupse B, Maedler K (2018) Hippo signaling: key emerging pathway in cellular and whole-body metabolism. Trends Endocrinol Metab 29:492–509
3. Bell CC, Hendriks DFG, Moro SML, Ellis E, Walsh J, Renblom A, Fredriksson Puigvert L, Dankers ACA, Jacobs F, Snoeys J et al (2016) Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci Rep 6:25187
4. Besse-Patin A, Léveillé M, Oropeza D, Nguyen BN, Prat A (2017) Estrogen signals through peroxisome proliferator-activated receptor−γ coactivator 1α to reduce oxidative damage associated with diet-induced fatty liver disease. Gastroenterology 152:243–256
5. Boardman HMP, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill Cosp X, Gabriel Sanchez R, Knight B (2015) Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015(3):CD002229