2. Academic Validation
  3. Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury

Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury

  • Metabolism. 2025 Aug:169:156275. doi: 10.1016/j.metabol.2025.156275.
Zhaodi Che 1,  Mingxiang Cai 2,  Xiaowu Dong 3,  Yuan Yuan 4,  Yaodong Wang 5,  Lu Xiao 1,  Yali Song 1,  Jiajun Zhong 1,  Pingping Luo 1,  Hao Wang 1,  Guotao Lu 6,  Yao Sun 7,  Jia Xiao 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 2 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.
  • 3 Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225009, China.
  • 4 Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Aier School of Ophthalmology, Central South University, Changsha 410083, China.
  • 5 Kunshan Hospital of Chinese Medicine, Kunshan Affiliated Hospital of Yangzhou University, Suzhou 215000, China.
  • 6 Institute of Digestive Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225009, China. Electronic address: gtlu@yzu.edu.cn.
  • 7 Department of Oral Implantology, School of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200092, China. Electronic address: yaosun@tongji.edu.cn.
  • 8 Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao 266000, China. Electronic address: edwinsiu@connect.hku.hk.
PMID: 40311841 DOI: 10.1016/j.metabol.2025.156275
Abstract

Aims: 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.

Methods and results: Hepatokine screening tests revealed that chronic-binge ethanol consumption upregulates hepatic AGT production, triggering downstream Ras activation. Hepatocyte-specific knockout of Agt (AGTΔHep) significantly alleviated ALD-induced liver injury. In organ screening between AGTflox/flox (AGTf/f) and AGTΔHep 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.

Conclusions: 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.

Keywords

Alcohol-associated liver disease; Alcoholic myopathy; Angiotensinogen; Hepatokine; Renin-angiotensin system.

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