RRC ID 78054
Author Seiya Yamada, Kazuhiko Nakadate, Tomoya Mizukoshi, Kiyoharu Kawakami, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Shin-ichi Sakakibara
Title Induction of NASH and vacuolar structures in the Nwd1−/− mouse liver via SERCA2-dependent endoplasmic reticulum stress
Abstract The endoplasmic reticulum (ER) stores Ca2+ and plays crucial roles in protein folding, lipid transfer, and the regulation of organelle dynamics. Perturbations in ER homeostasis, characterized by the accumulation of unfolded proteins, trigger an adaptive response termed ER stress. In the liver, chronic ER stress is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) with hepatic steatosis and lipid droplet formation. 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 of neural stem cells, as a co-chaperone in brain development. However, the physiological significance of this gene outside the central nervous system remains unclear. In this study, we revealed that Nwd1 knockout mice exhibited pathological manifestations comparable to NASH, including aberrant ER morphology, heightened lipid droplet formation, fibrosis, and pyroptosis. Electron microscopy revealed excessive lipid droplets encapsulated in vacuolar membranes derived from the ER in Nwd1−/− hepatocytes. Proteomic analysis, immunoelectron microscopy, and biochemical studies indicated that 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 liver homeostasis and the pathogenesis of NASH.
DOI 10.1101/2024.01.26.577307
Mice RBRC01828