Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing betaoxidation

• Published in: Clinical and molecular hepatology pp. 445 - 459
• Main Authors: Ester Ciociola, Tanmoy Dutta, Kavitha Sasidharan, Lohitesh Kovooru, Francesca R. Noto(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, Catanza), Grazia Pennisi(Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza, Salvatore Petta(Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza, Angela Mirarchi, Samantha Maurotti, Bernardette Scopacasa, Luca Tirinato, Patrizio Candeloro(Department of Experimental and Clinical Medicine, University of Magna Graecia, Catanzaro, Italy, Nanotechnology Research Center, Department of Experimental and Clinical Medicine, University of Magna Graecia, Catanzaro, Italy), Marcus Henricsson(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, R), Daniel Lindén(Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, Oveis Jamialahmadi, Arturo Pujia, Rosellina M. Mancina(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, Ro), Stefano Romeo(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, Ital)
• Format: Journal Article
• Language: English
• Published: 대한간학회 01.04.2025
• Subjects: 내과학
• ISSN: 2287-2728; 2287-285X
• DOI: 10.3350/cmh.2024.0642

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic. The disease 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 that promote this protection. Methods: We downregulated MARC1 in primary human hepatocytes (PHHs) using short interfering RNA (siRNA). We measured neutral lipid content by Oil-Red O staining and fatty acid oxidation by radiolabeled tracers. We also performed RNA-sequencing and proteomic analysis using LC-MS. Additionally, we analyzed data from 239,075 participants from the UK Biobank. Results: Downregulation of MARC1 reduced neutral lipid content in PHHs homozygous for the wild type (p.A165, risk), but not for the mutant (p.T165, protective), allele. We found that this reduction was mediated by increased fatty acid utilization via β-oxidation. Consistent with these results, we found that the levels of 3-hydroxybutyrate, a byproduct of β-oxidation, were higher in carriers of the rs2642438 minor allele among samples from the UK biobank, indicating higher β-oxidation in these individuals. Moreover, downregulation of the 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, while upregulating beneficial pathways involved in cell survival. KCI Citation Count: 0