MARC1 downregulation reduces hepatocyte lipid content by increasing beta-oxidation.

Autor:	Ciociola E; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Dutta T; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Sasidharan K; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Kovooru L; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Noto FR; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy., Pennisi G; Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy., Petta S; Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy., Mirarchi A; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy., Maurotti S; Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy., Scopacasa B; Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy., Tirinato L; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy., Candeloro P; Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy.; Nanotechnology Research Center, Department of Experimental and Clinical Medicine, University of Magna Graecia, 88100 Catanzaro, Italy., Henricsson M; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Biomarker Discovery and Development, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lindén D; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden., Jamialahmadi O; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Pujia A; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy., Mancina RM; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy.; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy., Romeo S; Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy.; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.; Department of Medicine, Huddinge Karolinska Institute, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	Clinical and molecular hepatology [Clin Mol Hepatol] 2024 Dec 23. Date of Electronic Publication: 2024 Dec 23.
DOI:	10.3350/cmh.2024.0642
Abstrakt:	Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic. MASLD has a strong genetic component, and a common missense variant (rs2642438) in the mitochondrial amidoxime-reducing component 1 (MARC1) gene confers protection against its onset and severity. However, there are contrasting results regarding the mechanisms entangling this protection. Methods: We downregulated MARC1 in primary human hepatocytes (PHH) using short interfering RNA (siRNA). Neutral lipid content was measured by Oil-Red O staining and fatty acid oxidation measured using radiolabeled tracers. RNA-seq and proteomic analysis using LC-MS were also performed. Additionally, we analyzed data from 239,075 participants from the UK Biobank. Results: Downregulation of MARC1 reduced neutral lipid content in PHH homozygous for the wild type (p.A165, risk) but not for the mutant (p.T165, protective) protein. Experimental results demonstrated that this reduction was mediated by an increased fatty acid utilization by beta-oxidation. Consistently, 3-hydroxybutyrate levels, a by-product of β-oxidation, were higher in carriers of the rs2642438 minor allele from the UK Biobank indicating higher β-oxidation in these individuals. Moreover, downregulation of MARC1 p.A165 variant resulted in a more favorable phenotype by reducing ferroptosis and reactive oxygen species levels. Conclusions: MARC1 downregulation in carriers of the risk allele results in lower hepatocyte neutral lipids content due to higher β-oxidation, and upregulates beneficial pathways for cell survival.
Databáze:	MEDLINE
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