Che Zhaodi, Cai Mingxiang, Dong Xiaowu, Yuan Yuan, Wang Yaodong, Xiao Lu, Song Yali, Zhong Jiajun, Luo Pingping, Wang Hao, Lu Guotao, Sun Yao, Xiao Jia
Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of Stomatology, Jinan University, Guangzhou 510630, China.
Metabolism. 2025 Aug;169:156275. doi: 10.1016/j.metabol.2025.156275. Epub 2025 Apr 29.
The organ communication mechanisms driven by alcohol-associated liver disease (ALD) remain inadequately understood. This study explores the endocrine roles of the hepatokine angiotensinogen (AGT) and the renin-angiotensin system (RAS) in ALD.
Hepatokine screening tests revealed that chronic-binge ethanol consumption upregulates hepatic AGT production, triggering downstream RAS activation. Hepatocyte-specific knockout of Agt (AGT) significantly alleviated ALD-induced liver injury. In organ screening between AGT (AGT) and AGT mice, skeletal muscle exhibited the most pronounced improvement in alcoholic myopathy (AM)-related phenotypes, including reduced muscle mass, enhanced oxidative stress, and mitochondrial dysfunction post-ethanol administration. Mechanistically, the renin-angiotensin axis transmits damaging signals from AGT to their membrane receptor AGTR1 in both hepatocytes and myocytes. Pharmacological inhibition of AGT, renin, and angiotensin-converting enzyme, as well as specific knockdown of Agtr1 in hepatocytes or myocytes, effectively attenuated both conditions. Activation of the counteractive axis of the RAS-AGTR1 pathway, involving Ang (1-7) and its membrane receptor MAS1, ameliorated the alcoholic injury of both the liver and muscle. Conversely, specific knockdown of Mas1 in hepatocytes and myocytes exacerbated these injuries.
Our work demonstrates that hepatokine AGT promotes ALD and AM through the activation of the RAS-AGTR1 axis and the inhibition of the Ang(1-7)-MAS1 axis, offering a foundation for concurrent therapeutic strategies for both diseases.
由酒精性肝病（ALD）驱动的器官通讯机制仍未得到充分理解。本研究探讨肝源细胞因子血管紧张素原（AGT）和肾素-血管紧张素系统（RAS）在ALD中的内分泌作用。
肝源细胞因子筛选试验显示，慢性暴饮乙醇会上调肝脏AGT的产生，触发下游RAS激活。肝细胞特异性敲除Agt（AGT）可显著减轻ALD诱导的肝损伤。在AGT（AGT）小鼠和野生型小鼠之间进行的器官筛选中，骨骼肌在酒精性肌病（AM）相关表型方面表现出最明显的改善，包括乙醇给药后肌肉质量减少、氧化应激增强和线粒体功能障碍。从机制上讲，肾素-血管紧张素轴将损伤信号从AGT传递到肝细胞和肌细胞中的膜受体AGTR1。对AGT、肾素和血管紧张素转换酶的药理抑制，以及在肝细胞或肌细胞中特异性敲低Agtr1，均有效减轻了这两种情况。RAS-AGTR1途径的拮抗轴（涉及Ang (1-7) 及其膜受体MAS1）的激活改善了肝脏和肌肉的酒精性损伤。相反，在肝细胞和肌细胞中特异性敲低Mas1会加剧这些损伤。
我们的研究表明，肝源细胞因子AGT通过激活RAS-AGTR1轴和抑制Ang(1-7)-MAS1轴促进ALD和AM，为这两种疾病的联合治疗策略提供了基础。
