Vitamin D Protects Against Alcohol-Induced Liver Cell Injury Within an NRF2-ALDH2 Feedback Loop

Scope Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Oxidative stress induced during the alcohol metabolism plays a crucial role in ALD, and clinical evidence demonstrates the prevalence and risks of vitamin D (VD) deficiency in ALD. This study aims to explore the mechanism of VD administration to ameliorate alcohol-induced cell injury. Methods and results VD activates NRF2 (nuclear factor erythroid 2 (NF-E2)-related factor 2) signals along with upregulation of ALDH2 expression. Knockdown of NRF2 eliminates the protective effects of VD treatment. ALDH2 knockdown not only partially affects this protection, but also mildly reduces NRF2 expression. ALDH2 overexpression enhances ERK phosphorylation and upregulated NRF2 transcription via a newly identified TRE in the exon 1 of NRF2. Conclusion This study provides evidence that VD protects against alcohol-induced cell injury within an NRF2-ALDH2 feedback loop. NRF2 induced by VD could transcriptionally upregulate ALDH2 expression to help metabolize alcohol. TRE-driven transcriptional upregulation of NRF2 through ALDH2-ERK/MEK signals would further exert the anti-oxidant effects. The study explores a novel potential protection of VD in alcohol-induced liver cell injury, and contributes to alcohol-related liver disease nutritional therapies.