Metabolism: clinical and experimental · 2025
Angiotensinogen inhibition concurrently mitigates alcohol-associated hepatic and muscle injury.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.