ArticleMolecular metabolism2025
Membrane-associated ring-CH-type finger 2 protects against metabolic dysfunction-associated fatty liver disease by targeting fatty acid synthase.
Article in Molecular metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
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- PCSK9 inhibitors do not increase cognitive risk.Biology direct · 2026Article
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10 authors.
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Abstract
objectiveMetabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as an important public health concern that poses a significant threat to human health and imposes a substantial economic burden. Research has demonstrated that ubiquitin ligase-mediated substrate protein ubiquitination is a pivotal factor influencing liver lipid homeostasis and metabolic abnormalities in MAFLD. Nevertheless, the specific enzyme molecules implicated in this regulatory process remain to be elucidated. We have published a transcriptome-overexpressing ubiquitin ligase, membrane-associated ring-CH-type finger 2 (MARCH2), in HepG2 cells, and subsequent reanalysis of these transcriptome data revealed a close association between MARCH2 and lipid metabolism.
methodsBy employing a range of methodologies, including recombinant adeno-associated virus (rAAV) transduction, lentiviral transduction, immunoblotting, quantitative PCR, tissue section staining, ubiquitination assays, serum biochemical analysis, immunoprecipitation, and mass spectrometry, this study investigated the functions and mechanisms of MARCH2 in the progression of MAFLD at the molecular, cellular, and organismal levels.
resultsOverexpression of MARCH2, but not its catalytically inactive ligase variant, inhibited lipid accumulation in HepG2 cells. Additionally, MARCH2 undergoes K48-linked self-polyubiquitination and subsequent proteasomal degradation in response to oleic acid/palmitic acid stimulation. Furthermore, knockout of MARCH2 exacerbates the progression of MAFLD-related phenotypes, including increased body weight, impaired glucose tolerance, reduced insulin sensitivity, hypercholesterolemia, hepatic lipid accumulation, and steatosis, in high-fat diet-fed mice, irrespective of sex. Mechanistically, MARCH2 facilitates the polyubiquitination and degradation of fatty acid synthase (FASN) in the de novo lipogenesis pathway. And liver-specific overexpression of MARCH2 by rAAV effectively reduces FASN levels and further ameliorates MAFLD in ob/ob mice.
conclusionsMARCH2 undergoes self-ubiquitination and plays an important role in maintaining the liver lipid homeostasis of MAFLD, and drug intervention in the MARCH2-FASN axis is a promising approach for treating systemic metabolic abnormalities in MAFLD.
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