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。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-04-01 Epub Date: 2024-03-08 DOI:10.1038/s44320-024-00024-x
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
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引用次数: 0

摘要

肥胖相关肝脏恶性肿瘤的性别差异表明雌激素具有保护作用。我们利用临床前模型,通过整合肝脏多组学数据,剖析了雌激素受体(ER)同工酶在雌雄小鼠接受或不接受雌激素激动剂治疗的高脂饮食(HFD)诱导的肝脏疾病中的分子反应。我们发现,选择性ER激活可恢复HFD诱导的肝脏分子和生理表型。HFD和全身性ER激活改变了核心肝脏通路,而不仅仅是脂质代谢,这在小鼠和灵长类动物之间是一致的。通过纳入患者队列数据,我们发现ER调节的增强子控制着代谢功能障碍相关性脂肪性肝病(MASLD)患者中具有临床意义的中心调控和代谢基因,包括转录因子TEAD1。TEAD1在MASLD患者中的表达增加,通过短干扰RNA对其进行下调可降低细胞内脂质含量。随后的 TEAD 小分子抑制剂通过抑制脂肪生成途径,改善了原代人类肝细胞球体的脂肪变性。因此,TEAD1 成为一种新的候选疗法,其抑制作用可改善肝脂肪变性。
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Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.

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.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
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.
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