PUBLICATION
Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
- Authors
- Shan, M., Apolinario, M.E.C., Tokumaru, T., Shikano, K., Phurpa, P., Kato, A., Teranishi, H., Kume, S., Shimizu, N., Kurokawa, T., Hikida, T., Hanada, T., Li, Y., Hanada, R.
- ID
- ZDB-PUB-260129-32
- Date
- 2026
- Source
- International Journal of Molecular Sciences 27: (Journal)
- Registered Authors
- Hanada, Reiko, Hanada, Toshikatsu
- Keywords
- GRABAdo sensor, extracellular adenosine (eAdo), metabolic dysfunction-associated steatotic liver disease (MASLD), vitamin E, zebrafish model
- MeSH Terms
-
- Adenosine*/metabolism
- Animals
- Animals, Genetically Modified
- Disease Models, Animal
- Endoplasmic Reticulum Stress/drug effects
- Fatty Liver*/drug therapy
- Fatty Liver*/metabolism
- Liver*/drug effects
- Liver*/metabolism
- Liver*/pathology
- Non-alcoholic Fatty Liver Disease*/metabolism
- Signal Transduction*/drug effects
- Vitamin E*/pharmacology
- Zebrafish
- PubMed
- 41596272 Full text @ Int. J. Mol. Sci.
Citation
Shan, M., Apolinario, M.E.C., Tokumaru, T., Shikano, K., Phurpa, P., Kato, A., Teranishi, H., Kume, S., Shimizu, N., Kurokawa, T., Hikida, T., Hanada, T., Li, Y., Hanada, R. (2026) Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences. 27:.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRABAdo). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco/ER Ca2+-ATPase (SERCA) machinery, which is essential for maintaining ER Ca2+ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca2+-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca2+ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping