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

Abstract

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.

Vitamin D confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

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Vitamin D Deficiency Aggravates Hepatic Oxidative Stress and Inflammation during Chronic Alcohol-Induced Liver Injury in Mice

“…In contrast, a recent study reported that vitamin D attenuated alcohol-induced HepG2 cell injury partially by upregulating ALDH2 expression [23]. One possible explanation for this discrepancy could be that in our study, we only focus our attention on the activity of ALDH.…”

Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms

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