YAP在小鼠禁食-再喂食转变过程中调节肝脏大小。

YAP regulates the liver size during the fasting-refeeding transition in mice.

作者信息

Li Xuan, Fan Shicheng, Cai Chenghui, Gao Yue, Wang Xinhui, Zhang Yifei, Liang Hangfei, Li Huilin, Yang Jie, Huang Min, Bi Huichang

机构信息

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

出版信息

Acta Pharm Sin B. 2023 Apr;13(4):1588-1599. doi: 10.1016/j.apsb.2022.12.011. Epub 2022 Dec 21.

Abstract

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV (5SA) mice. overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV shRNA mice. knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

摘要

肝脏是进食-禁食转换期间调节能量代谢的核心枢纽。有证据表明,禁食和重新进食会引起肝脏大小的动态变化,但其潜在机制仍不清楚。Yes相关蛋白(YAP)是器官大小的关键调节因子。本研究旨在探讨YAP在禁食和重新进食诱导的肝脏大小变化中的作用。在此,禁食显著减小了肝脏大小,重新进食后恢复到正常水平。此外,禁食后肝细胞大小减小,肝细胞增殖受到抑制。相反,与禁食状态相比,重新进食促进了肝细胞的增大和增殖。从机制上讲,禁食或重新进食调节了YAP及其下游靶点的表达,以及增殖相关蛋白细胞周期蛋白D1(CCND1)的表达。此外,禁食显著减小了AAV对照小鼠的肝脏大小,而在AAV(5SA)小鼠中这种减小得到缓解。YAP过表达也阻止了禁食对肝细胞大小和增殖的影响。此外,在AAV shRNA小鼠中,重新进食后肝脏大小的恢复延迟。YAP敲低减弱了重新进食诱导的肝细胞增大和增殖。总之,本研究表明YAP在禁食-重新进食转换期间肝脏大小的动态变化中起重要作用,这为YAP在能量应激下调节肝脏大小提供了新证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc36/10149903/0221ffb79aa4/ga1.jpg

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