Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury

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 (AGT^ΔHep) significantly alleviated ALD-induced liver injury. In organ screening between AGT^flox/flox (AGT^f/f) and AGT^ΔHep 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.