ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH
Enhancing NAD<sup>+</sup> levels has been shown to induce remarkable health benefits in mouse models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), yet liver-specific NAD<sup>+</sup> boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance de novo synthesis of NAD<sup>+</sup> in the liver by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD<sup>+</sup> levels, enhances mitochondrial respiration, and maintains genomic stability in hepatocytes ex vivo and in vivo. These molecular benefits prevent disease progression in both mouse and human liver organoid models of steatohepatitis. Our preclinical study identifies ACMSD as a promising target for MASLD/MASH management and lays the groundwork for developing ACMSD inhibitors as a clinical treatment.
Authors
- Sandra Rodríguez-López
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Riekelt H. Houtkooper (ORCID: https://orcid.org/0000-0001-9961-0842)
- Takanori Takebe (ORCID: https://orcid.org/0000-0002-6989-3041)
- Xiaoxu Li (ORCID: https://orcid.org/0000-0001-5121-9190)
- Angelique M. L. Scantlebery (ORCID: https://orcid.org/0000-0001-9303-6042)
- Yasmine J. Liu (ORCID: https://orcid.org/0000-0002-6830-8023)
- Jonathan Sulc (ORCID: https://orcid.org/0000-0002-5572-6541)
- Julijana Ivanišević (ORCID: https://orcid.org/0000-0001-8267-2705)
- Archana Vijayakumar
- Héctor Gallart‐Ayala (ORCID: https://orcid.org/0000-0003-2333-0646)
- G. Mani Subramanian (ORCID: https://orcid.org/0000-0002-5506-9609)
- Keno Strotjohann (ORCID: https://orcid.org/0009-0003-3675-3039)
- Qi Wang (ORCID: https://orcid.org/0000-0002-9239-1998)
- Masaki Kimura (ORCID: https://orcid.org/0000-0001-5530-2629)
- Robert P. Myers
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Amsterdam Neuroscience (NL)
- ATUM (United States) (US)
- Amsterdam University Medical Centers (NL)
- Osaka University Hospital (JP)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Amsterdam (NL)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Hepatology
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1016/j.jhep.2024.08.009
- Citations
- 25
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- National Science Foundation
- European Molecular Biology Organization
- BrightFocus Foundation
- European Commission
- National Research Foundation
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Research Foundation of Korea
- Université de Lausanne
- National Institutes of Health
- Horizon 2020 Framework Programme
- HORIZON EUROPE Framework Programme
- HORIZON EUROPE European Research Council