PT - JOURNAL ARTICLE AU - Yamada, Seiya AU - Nakadate, Kazuhiko AU - Mizukoshi, Tomoya AU - Kawakami, Kiyoharu AU - Kobayashi, Ryosuke AU - Horii, Takuro AU - Hatada, Izuho AU - Sakakibara, Shin-ichi TI - Induction of NASH in the <em>Nwd1<sup>−/−</sup></em> mouse liver via SERCA2-dependent endoplasmic reticulum stress AID - 10.1101/2024.01.26.577307 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.01.26.577307 4099 - http://biorxiv.org/content/early/2024/01/30/2024.01.26.577307.short 4100 - http://biorxiv.org/content/early/2024/01/30/2024.01.26.577307.full AB - The 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 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.HighlightsNwd1−/− mice exhibited NASH-like liver steatosis.Elevated ER stress, fibrosis, and pyroptosis were observed in Nwd1−/− livers.Nwd1 interacts with SERCA2, an ER membrane Ca2+ pump.Nwd1−/− livers exhibited reduced SERCA2 activity and smaller Ca2+ pools in the ER.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsERendoplasmic reticulumNAFLDnonalcoholic fatty liver diseaseNASHnonalcoholic steatohepatitisSERCA2sarco/endoplasmic reticulum calcium ATPaseNwd1NACHT and WD repeat domain-containing protein 1VLDLvery low-density lipoproteinSTANDsignal transduction ATPases with numerous domainsNSPCsneural stem/progenitor cellsssODNssingle-stranded oligodeoxynucleotidesDMEMDulbecco’s Modified Eagle MediumPFAparaformaldehydeGAglutaraldehydePBphosphate bufferPASperiodic acid-SchiffHRPhorseradish peroxidaseGOGene OntologyKEGGKyoto Encyclopedia of Genes and GenomesTMtunicamycinHEhematoxylin and eosinANT2ADP/ATP translocase 2VDACvoltage-dependent anion-selective channel protein 1ATF6activating transcription factor 6