Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI:10.1242/dmm.050900
Mingkai Zhu, Yan Li, Qiaosen Shen, Zhiyuan Gong, Dong Liu
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Abstract

Partial hepatectomy (PH) is commonly used to treat patients with hepatocellular carcinoma. The recovery of patients from PH depends on the initiation of liver regeneration, a process that mainly relies on liver cell proliferation. As sex affects the human liver regeneration progress, we investigated sex disparity in PH-induced liver regeneration in adult zebrafish. We found that, after PH, males began liver regeneration earlier than females in terms of liver cell proliferation and liver mass recovery, and this was associated with earlier activation of Yap1 signaling in male than female livers. We also found that androgen receptors regulated the sex-biased liver regeneration in a Yap1-dependent manner and that activated estrogen receptors are responsible for the later onset of female hepatocyte proliferation. Furthermore, we identified that S100A1, a calcium-binding protein, regulates the sex disparity in liver regeneration, as heterozygous S100A1 knockout inhibited Yap1 activity in male livers and delayed hepatocyte proliferation in males following PH. Thus, multiple pathways and/or their interplays contribute to the sex disparity in liver regeneration, suggesting that sex-biased therapeutic strategies are required for patients who have received PH-based therapies.

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肝部分切除术后斑马鱼肝细胞增殖的性别差异受性激素受体和 S100A1-YAP 信号级联的调控。
肝部分切除术(PH)是治疗肝细胞癌患者的常用方法。肝切除术后患者的康复取决于肝脏再生的正确启动,而这一过程主要依赖于肝细胞的增殖。由于性别会影响人类肝脏再生的进程,我们研究了成年斑马鱼在 PH 诱导的肝脏再生过程中如何实现性别差异。我们发现,在肝细胞增殖和肝脏质量恢复方面,雄性斑马鱼比雌性斑马鱼更早开始肝脏再生。这种性别差异与雄性肝脏中更早的 YAP 信号激活有关。我们还发现,雄激素受体以依赖YAP的方式调控性别差异的肝脏再生,而活化的雌激素受体是女性肝细胞增殖开始较晚的原因。此外,研究还发现钙结合蛋白S100A1可调控肝脏再生的性别差异,因为杂合子S100A1敲除可抑制男性肝脏中YAP的活性,并延缓PH后男性肝细胞的增殖。因此,目前的研究表明,多种途径和/或它们之间的相互作用导致了肝脏再生的性别差异。我们的研究结果表明,要帮助接受PH疗法的患者,需要制定精细的、基于性别的治疗策略。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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