Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage.

IF 12.9 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Irene González-Recio, Naroa Goikoetxea-Usandizaga, Claudia M Rejano-Gordillo, Carolina Conter, Rubén Rodríguez Agudo, Marina Serrano-Maciá, Leidy Estefanía Zapata-Pavas, Patricia Peña-Sanfélix, Mikel Azkargorta, Félix Elortza, José María Herranz, Álex Guillamon Thiery, Armando Raúl Guerra-Ruiz, Ramiro Jover, Unai Galicia-Garcia, César Martín, Ute Schaeper, Teresa C Delgado, Irene Díaz-Moreno, Antonio Díaz Quintana, Daniela Buccella, Rubén Nogueiras, JosepMaria Argemi, Matías A Ávila, Jordi Gratacós-Ginès, Paula Iruzubieta, Elisa Pose, Ramón Bataller, Javier Crespo, Luis Alfonso Martínez-Cruz, María Luz Martínez-Chantar
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引用次数: 0

Abstract

Background and aims: Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg 2+ ) deficiency, which can influence liver disease progression. The mechanisms underlying Mg 2+ homeostasis dysregulation in ALD remain elusive. This study aimed to investigate the role of the Mg 2+ transporter Cyclin M4 (CNNM4) in ALD by analyzing its expression patterns in patients with ALD and preclinical animal models.

Approach and results: In this study, CNNM4 is upregulated in the liver of both patients with ALD and animal models. CNNM4 overexpression triggers Mg 2+ homeostasis dysregulation, linked to ALD progression. We propose a novel therapeutic approach for ALD treatment using N -acetylgalactosamine silencing RNA technology to specifically modulate Cnnm4 expression in the liver, improving mitochondrial function and alleviating endoplasmic reticulum stress. Notably, silencing Cnnm4 restores protein isoaspartyl methyltransferase (PCMT1) activity, essential for repairing ethanol-induced protein damage. Enhancing mitochondrial activity through Cnnm4-dependent mechanisms increases S -adenosylmethionine levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD treatment.

Conclusions: These findings shed light on the dysregulation of Mg 2+ homeostasis in ALD, providing a promising therapeutic approach targeting CNNM4. N -acetylgalactosamine si Cnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1 activity.

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来源期刊
Hepatology
Hepatology 医学-胃肠肝病学
CiteScore
27.50
自引率
3.70%
发文量
609
审稿时长
1 months
期刊介绍: HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.
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