Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver
Abstract Endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and it’s perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic d...
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07717-5 |
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| author | Seiya Yamada Hayato Ogawa Miona Funato Misaki Kato Kazuhiko Nakadate Tomoya Mizukoshi Kiyoharu Kawakami Ryosuke Kobayashi Takuro Horii Izuho Hatada Shin-ichi Sakakibara |
| author_facet | Seiya Yamada Hayato Ogawa Miona Funato Misaki Kato Kazuhiko Nakadate Tomoya Mizukoshi Kiyoharu Kawakami Ryosuke Kobayashi Takuro Horii Izuho Hatada Shin-ichi Sakakibara |
| author_sort | Seiya Yamada |
| collection | DOAJ |
| description | Abstract Endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and it’s perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of Ca2+ transport from the cytosol to ER, is associated with the induction of ER stress and lipid droplet formation. We previously identified NACHT and WD repeat domain-containing protein 1 (Nwd1) localized at the ER and mitochondria. However, the physiological significance of Nwd1 outside the brain remains unclear. In this study, we revealed that Nwd1 −/− mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. Nwd1 −/− livers exhibited reduced SERCA2 ATPase activity and a smaller Ca2+ pool in the ER, leading to an exacerbated state of ER stress. These findings highlight the importance of SERCA2 activity mediated by Nwd1 in the pathogenesis of MASH. |
| format | Article |
| id | doaj-art-b23ee3d8b0ff4b6da4ef11682ac0a6a0 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-b23ee3d8b0ff4b6da4ef11682ac0a6a02025-08-20T03:01:45ZengNature PortfolioCommunications Biology2399-36422025-03-018111610.1038/s42003-025-07717-5Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liverSeiya Yamada0Hayato Ogawa1Miona Funato2Misaki Kato3Kazuhiko Nakadate4Tomoya Mizukoshi5Kiyoharu Kawakami6Ryosuke Kobayashi7Takuro Horii8Izuho Hatada9Shin-ichi Sakakibara10Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityLaboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityLaboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityLaboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityDepartment of Functional Morphology, Meiji Pharmaceutical UniversityLaboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityDepartment of Functional Morphology, Meiji Pharmaceutical UniversityLaboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma UniversityLaboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma UniversityLaboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma UniversityLaboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda UniversityAbstract Endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and it’s perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of Ca2+ transport from the cytosol to ER, is associated with the induction of ER stress and lipid droplet formation. We previously identified NACHT and WD repeat domain-containing protein 1 (Nwd1) localized at the ER and mitochondria. However, the physiological significance of Nwd1 outside the brain remains unclear. In this study, we revealed that Nwd1 −/− mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. Nwd1 −/− livers exhibited reduced SERCA2 ATPase activity and a smaller Ca2+ pool in the ER, leading to an exacerbated state of ER stress. These findings highlight the importance of SERCA2 activity mediated by Nwd1 in the pathogenesis of MASH.https://doi.org/10.1038/s42003-025-07717-5 |
| spellingShingle | Seiya Yamada Hayato Ogawa Miona Funato Misaki Kato Kazuhiko Nakadate Tomoya Mizukoshi Kiyoharu Kawakami Ryosuke Kobayashi Takuro Horii Izuho Hatada Shin-ichi Sakakibara Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver Communications Biology |
| title | Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver |
| title_full | Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver |
| title_fullStr | Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver |
| title_full_unstemmed | Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver |
| title_short | Induction of MASH-like pathogenesis in the Nwd1 −/− mouse liver |
| title_sort | induction of mash like pathogenesis in the nwd1 mouse liver |
| url | https://doi.org/10.1038/s42003-025-07717-5 |
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