Modulatory effects of CNNM4 on protein-L-isoaspartylO-methyltransferase repair function during alcohol-induced hepatic damage
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 (Mg2+) deficiency, which can,influence liver disea...
| Autores: | , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/174220 |
| Acceso en línea: | https://hdl.handle.net/11441/174220 https://doi.org/10.1097/HEP.0000000000001156 |
| Access Level: | acceso abierto |
| Palabra clave: | Alcohol ALD Hepatotoxicity Magnesium |
| Sumario: | 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 (Mg2+) deficiency, which can,influence liver disease progression. The mechanisms underlying Mg2+,homeostasis dysregulation in ALD remain elusive. This study aimed to,investigate the role of the Mg2+ 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 Mg2+ 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 Mg2+,homeostasis in ALD, providing a promising therapeutic approach targeting,CNNM4. N-acetylgalactosamine siCnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1,activity. |
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