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Article

Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by
Mengting Shan
1,
Magdeline E. Carrasco Apolinario
1,
Tomoko Tokumaru
2,
Kenshiro Shikano
1,
Phurpa Phurpa
1,
Ami Kato
1,
Hitoshi Teranishi
1,
Shinichiro Kume
1,
Nobuyuki Shimizu
3,
Tatsuki Kurokawa
1,
Takatoshi Hikida
4,
Toshikatsu Hanada
3,
Yulong Li
5 and
Reiko Hanada
1,*
1
Department of Physiology, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan
2
Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan
3
Department of Biochemistry and Molecular Genetics, Faculty of Medicine, Oita University, Yufu 879-5593, Oita, Japan
4
Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita 565-0871, Osaka, Japan
5
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(2), 614; https://doi.org/10.3390/ijms27020614
Submission received: 28 November 2025 / Revised: 2 January 2026 / Accepted: 4 January 2026 / Published: 7 January 2026
(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)
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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.
Keywords: metabolic dysfunction-associated steatotic liver disease (MASLD); vitamin E; extracellular adenosine (eAdo); GRABAdo sensor; zebrafish model metabolic dysfunction-associated steatotic liver disease (MASLD); vitamin E; extracellular adenosine (eAdo); GRABAdo sensor; zebrafish model

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MDPI and ACS Style

Shan, M.; Apolinario, M.E.C.; Tokumaru, T.; Shikano, K.; Phurpa, P.; Kato, A.; Teranishi, H.; Kume, S.; Shimizu, N.; Kurokawa, T.; et al. Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Int. J. Mol. Sci. 2026, 27, 614. https://doi.org/10.3390/ijms27020614

AMA Style

Shan M, Apolinario MEC, Tokumaru T, Shikano K, Phurpa P, Kato A, Teranishi H, Kume S, Shimizu N, Kurokawa T, et al. Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences. 2026; 27(2):614. https://doi.org/10.3390/ijms27020614

Chicago/Turabian Style

Shan, Mengting, Magdeline E. Carrasco Apolinario, Tomoko Tokumaru, Kenshiro Shikano, Phurpa Phurpa, Ami Kato, Hitoshi Teranishi, Shinichiro Kume, Nobuyuki Shimizu, Tatsuki Kurokawa, and et al. 2026. "Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)" International Journal of Molecular Sciences 27, no. 2: 614. https://doi.org/10.3390/ijms27020614

APA Style

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(2), 614. https://doi.org/10.3390/ijms27020614

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