ArticleLiver international : official journal of the International Association for the Study of the Liver2024
Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.
Article in Liver international : official journal of the International Association for the Study of the Liver, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 15 citations in OpenAlex.
- Prime editing models the MTARC1 A165T variant in human liver organoids, demonstrating reduced steatosis, inflammation, and fibrosis.Hepatology communications · 2026Article
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- MTARC1 p.A165 ablation reduces hepatocellular carcinoma aggressiveness in vitro and in vivo.Clinical and molecular hepatology · 2026Article
- Correspondence to editorial on "Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation".Clinical and molecular hepatology · 2026Article
- Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- A mitochondrial amidoxime-reducing component 1 (mARC1) A168T amino acid substitution does not confer protection from MASH and fibrosis in multiple mouse models of chronic liver disease.The Biochemical journal · 2026Article
- Ubiquitination and ubiquitin-like modifications in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications.BMB reports · 2025Review
- Gene-based therapies for steatotic liver disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation.Clinical and molecular hepatology · 2025Article
- Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease.Clinical and molecular hepatology · 2025Review
- NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review.International journal of molecular sciences · 2024Review
- Letter regarding 'mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome'.Liver international : official journal of the International Association for the Study of the Liver · 2024Article
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Authors and funding
14 authors at 5 institutions in 6 countries.
Funding
Abstract
objectiveMetabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization.
methodsWe overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization.
resultsMARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization.
conclusionsThis study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
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