Unveiling the Link Between Neddylation and Hepatic Zonation: Key Insights Into Liver Metabolism and Diseases - European Medical Journal

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Unveiling the Link Between Neddylation and Hepatic Zonation: Key Insights Into Liver Metabolism and Diseases

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Hepatology
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Authors:
Giselle Adriana Abruzzese , 1 Naroa Goikoetxea-Usandizaga , 1,2 Leidy Estefanía Zapata-Pavas , 1 Marcos Fernandez Fondevila , 3,4 Abhishek Murti , 5 Ana Belen Plata Gomez , 6 Bruce Wang , 5 Alejo Efeyan , 6 Ruben Nogueiras , 3,4 * María Luz Martínez-Chantar 1,2
  • 1. Liver Disease Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain
  • 2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
  • 3. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela, Spain
  • 4. Instituto de Investigación Sanitaria, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
  • 5. Department of Medicine, University of California San Francisco Medical Center, USA
  • 6. Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre, Madrid, Spain
*Correspondence to [email protected]
Disclosure:

Abruzzese is supported by an MSCA Postdoctoral Fellowship; and received a full bursary to attend EASL 2025 from the organisation. Efeyan has received support for the present manuscript from the LaCaixa Foundation and Agencia Estatal de Investigación. All other authors have declared no conflicts of interest.

Acknowledgements:

The authors would like to acknowledge Agustina Creus for her technical support.

Citation:
EMJ Hepatol. ;13[1]:38-39. https://doi.org/10.33590/emjhepatol/VMMF5290.
Keywords:
Liver zonation, metabolic zonation, neddylation.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

The liver exhibits metabolic zonation, with gene expression and metabolic functions distributed across specific zones along the lobule radial axis.1,2 Disruption of zonation is linked to the initiation and progression of liver pathologies. Neddylation, a post-translational modification essential for metabolism, influences zonal metabolic processes and is associated with liver pathogenesis.3 However, its relationship with liver zonation remains understudied. This study aims to investigate the connection between neddylation and liver zonation, evaluating its metabolic implications and role in liver diseases.

METHOD

Spatial transcriptomics was used to assess the localisation of neddylation machinery gene expression in mice. Biotinylated ubiquitin and biotinylated NEDD8 mice were employed to evaluate post-translational modifications in known zonated proteins. The authors also utilised different transgenic mouse models to study: 1) the impact of zonation loss on neddylation using LiTSC1KO RagAGTP mutants,4 which exhibit zonation disruption without hepatic disease at early stages; and 2) the role of neddylation modulation on zonation, using models that silence or overexpress NEDD8, silence NAE1 (a key NEDD8 activator), or overexpress SENP8 (a major deneddylation protease).

RESULTS

Neddylation genes were more highly expressed in pericentral hepatocytes than periportal ones. Proteomic data from biotinylated NEDD8 and biotinylated ubiquitin mice revealed neddylation and ubiquitination enrichment on periportal zonation markers (e.g., ALB, ASS, ASL, CYP2F2). In LiTSC1KO RagAGTP mutant mice, zonation loss altered the expression of neddylation mediators. Immunofluorescence showed a decentralised pattern of NEDD8 in the mutants compared to its periportal localisation in controls. Silencing NAE1 or overexpressing SENP8 (which encodes the deneddylase NEDP1) disrupted periportal marker gene expression, while NEDD8 modulation also affected central zone markers’ mRNA levels. Mutant models showed altered expression of genes involved in zonated metabolic processes, with pronounced effects when NEDD8 or NAE1 were manipulated.

CONCLUSION

The results demonstrate a significant association between neddylation and liver zonation, suggesting a zonal expression pattern of the neddylation machinery. Genetic manipulation of neddylation mediators influenced zonal markers and altered the expression of genes involved in zonated metabolic processes, reinforcing the link between neddylation and liver zonation (Figure 1). Future research will explore zonal neddylation modulation to elucidate its role in liver metabolism and pathology.

Figure 1: Schematic representation of the relationship between neddylation and liver zonation.

References
Abruzzese GA et al. Unveiling the link between neddylation and hepatic zonation: key insights into liver metabolism and diseases. Abstract number 986. EASL Congress, 7-10 May, 2025. Paris J, Henderson NC. Liver zonation, revisited. Hepatology. 2022;76(4):1219-30. Gonzalez-Rellan MJ et al. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Cell Metab. 2023;35(9):1630-45.e5. Plata-Gómez AB et al. Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver. Nat Commun. 2024;15(1):1878.

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