Induction of NASH and vacuolar structures in the Nwd1-/- mouse liver via SERCA2-dependent endoplasmic reticulum stress

The endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and its perturbations trigger an ER stress. In the liver, chronic ER stress is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Previous studies revealed that dysfunction of sarco/endoplasmic reticulum calcium ATPase (SERCA2), a key regulator of Ca2+ transport from the cytosol to the 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), which is localized in the ER and mitochondria. However, the physiological significance of Nwd1 outside the central nervous system remains unclear. In this study, we revealed that Nwd1 knockout mice exhibited pathological manifestations comparable to NASH. 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 NASH. HighlightsO_LINwd1-/- mice exhibited NASH-like liver steatosis. C_LIO_LIElevated ER stress, fibrosis, and pyroptosis were observed in Nwd1-/- livers. C_LIO_LINwd1 interacts with SERCA2, an ER membrane Ca2+ pump. C_LIO_LINwd1-/- livers exhibited reduced SERCA2 activity and smaller Ca2+ pools in the ER. C_LI