Induction of SIRT1 by melatonin improves alcohol‐mediated oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway
Open accessAbstract
Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin‐induced SIRT1 signaling protects against alcohol‐mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro‐inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol‐challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol‐fed WT mice but not in Cb1r antagonist‐treated, Crbn null, or Yy1‐silenced mice. Importantly, alcohol‐induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin‐SIRT1 signaling ameliorates alcohol‐induced oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway. The manipulation of CRBN‐YY1‐CYP2E1 signaling network by the melatonin‐SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease.
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Activation of SIRT1 by resveratrol and its synthetic structural derivatives and melatonin may prevent adduct formation and AGE-associated disease conditions.
“Thus, activation of SIRT1 by resveratrol and its synthetic structural derivatives288,289 and melatonin290 may prevent adduct formation and AGE-associated disease conditions.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [290]
Consumption of anti-inflammatory antioxidants from natural dietary supplements and/or synthetic origins can help reduce the incidence and severity of AGE-associated inflammation and related disorders.
“Furthermore, consumption of anti-inflammatory antioxidants from natural dietary supplements279,281,282,290 and/or synthetic origins199 can help reduce the incidence and severity of AGE-associated inflammation and related disorders.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [290]
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- Authors
- Lee, S., Koh, H., Joo, D. J., Nedumaran, B., Jeon, H., Park, C., Harris, R. A., & Kim, Y. D.
- Affiliations
- Kyungpook National University (KR)
- Yonsei University (KR)
- University of Colorado Anschutz (US)
- Gwangju Institute of Science and Technology (KR)
- Indiana University Indianapolis (US)
- Corresponding author
- Kim, Yong Deuk
- ORCID
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2020-02-28
- Volume
- 68
- Issue
- 3
- Pages
- e12638-e12638
- ISSN
- 0742-3098 (ISSN-L)
- 1600-079X
- OpenAlex
- W3006608178
- Cited by
- 48
- References
- 34
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 13 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 3
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Journal of Pineal Research (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea (2017R1D1A3A03000685)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- melatonin, SIRT1, alcoholic liver disease, oxidative liver damage, cereblon, YY1, CYP2E1, CB1 receptor, reactive oxygen species, alcohol-induced liver injury, hepatoprotection
- MeSH terms
- Animals, Humans, Liver Diseases, Alcoholic, Melatonin, Signal Transduction, Oxidative Stress, Cytochrome P-450 CYP2E1, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, YY1 Transcription Factor, Mice, Sirtuin 1
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