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<p>Endoplasmic reticulum (ER) stores Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 <i>Nwd1</i><sup><i>−/−</i></sup> mice exhibited pathological manifestations comparable to MASH. Nwd1 interacts with SERCA2 near ER membranes. <i>Nwd1</i><sup><i>−/−</i></sup> livers exhibited reduced SERCA2 ATPase activity and a smaller Ca<sup>2+</sup> 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.</p><p></p>

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Induction of MASH-like pathogenesis in the Nwd1−/− mouse liver

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月11日

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  • Seiya Yamada,
  • Hayato Ogawa,
  • Miona Funato,
  • Misaki Kato,
  • Kazuhiko Nakadate,
  • Tomoya Mizukoshi,
  • Kiyoharu Kawakami,
  • Ryosuke Kobayashi,
  • Takuro Horii,
  • Izuho Hatada,
  • Shin-ichi Sakakibara

摘要

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.