Metabolism. 2025 Apr 29:156275. doi: 10.1016/j.metabol.2025.156275. Online ahead of print.
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 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.
PMID:40311841 | DOI:10.1016/j.metabol.2025.156275