ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH
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| Title: | ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH |
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| Authors: | Yasmine J. Liu, Masaki Kimura, Xiaoxu Li, Jonathan Sulc, Qi Wang, Sandra Rodríguez-López, Angelique M.L. Scantlebery, Keno Strotjohann, Hector Gallart-Ayala, Archana Vijayakumar, Robert P. Myers, Julijana Ivanisevic, Riekelt H. Houtkooper, G. Mani Subramanian, Takanori Takebe, Johan Auwerx |
| Source: | J Hepatol Journal of hepatology, vol. 82, no. 2, pp. 174-188 |
| Publisher Information: | Elsevier BV, 2025. |
| Publication Year: | 2025 |
| Subject Terms: | Male, Liver Cirrhosis, Inflammation, Carboxy-Lyases, NAD, Animals, Mice, Humans, DNA Damage/drug effects, Carboxy-Lyases/antagonists & inhibitors, Carboxy-Lyases/genetics, Carboxy-Lyases/metabolism, Fatty Liver/metabolism, Fatty Liver/drug therapy, Fatty Liver/pathology, Mice, Inbred C57BL, Liver Cirrhosis/metabolism, Liver Cirrhosis/drug therapy, NAD/metabolism, Hepatocytes/metabolism, Hepatocytes/drug effects, Inflammation/metabolism, Disease Models, Animal, Liver/pathology, Liver/metabolism, Non-alcoholic Fatty Liver Disease/metabolism, Non-alcoholic Fatty Liver Disease/drug therapy, ACMSD, DNA repair, MASLD/MASH, Mendelian randomization, NAD(+), human liver organoids, Article, Fatty Liver, Liver, Non-alcoholic Fatty Liver Disease, Hepatocytes, DNA Damage |
| Description: | Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in the liver and kidney, acts as a modulator of de novo NAD+ synthesis. Boosting NAD+ levels has previously demonstrated remarkable metabolic benefits in mouse models. In this study, we aimed to investigate the therapeutic implications of ACMSD inhibition in the treatment of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH).In vitro experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and induced pluripotent stem cell-derived human liver organoids (HLOs). C57BL/6J male mice were fed a western-style diet and housed at thermoneutrality to recapitulate key aspects of MASLD/MASH. Pharmacological ACMSD inhibition was given therapeutically, following disease onset. HLO models of steatohepatitis were used to assess the DNA damage responses to ACMSD inhibition in human contexts.Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo, and in HLO models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; in humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibition of ACMSD in mice increases liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as observed in HLO models of steatohepatitis.Our findings highlight the benefits of ACMSD inhibition in enhancing hepatic NAD+ levels and enabling genomic protection, underscoring its therapeutic potential in MASLD/MASH.Enhancing NAD+ 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+ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance de novo synthesis of NAD+ in the liver by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD+ 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2024.08.009 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/39181211 https://serval.unil.ch/notice/serval:BIB_438655938954 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_4386559389544 https://serval.unil.ch/resource/serval:BIB_438655938954.P001/REF.pdf |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) ). |
| Accession Number: | edsair.doi.dedup.....b6d97004a7a6445bb62cae06f604b9f5 |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. The enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), primarily expressed in the liver and kidney, acts as a modulator of de novo NAD+ synthesis. Boosting NAD+ levels has previously demonstrated remarkable metabolic benefits in mouse models. In this study, we aimed to investigate the therapeutic implications of ACMSD inhibition in the treatment of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH).In vitro experiments were conducted in primary rodent hepatocytes, Huh7 human liver carcinoma cells and induced pluripotent stem cell-derived human liver organoids (HLOs). C57BL/6J male mice were fed a western-style diet and housed at thermoneutrality to recapitulate key aspects of MASLD/MASH. Pharmacological ACMSD inhibition was given therapeutically, following disease onset. HLO models of steatohepatitis were used to assess the DNA damage responses to ACMSD inhibition in human contexts.Inhibiting ACMSD with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo, and in HLO models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; in humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibition of ACMSD in mice increases liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage, as observed in HLO models of steatohepatitis.Our findings highlight the benefits of ACMSD inhibition in enhancing hepatic NAD+ levels and enabling genomic protection, underscoring its therapeutic potential in MASLD/MASH.Enhancing NAD+ 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+ boosting strategies remain underexplored. Here, we present a novel pharmacological approach to enhance de novo synthesis of NAD+ in the liver by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), an enzyme highly expressed in the liver. Inhibiting ACMSD increases NAD+ 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. |
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| ISSN: | 01688278 |
| DOI: | 10.1016/j.jhep.2024.08.009 |