Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice
The Journal of Nutrition
Available online 29 April 2023
Biochemical, Molecular, and Genetic Mechanisms in Nutrition
Ethan Baratz 1, Olga Protchenko 1, Shyamalagauri Jadhav 1, Deliang Zhang 2, Pierre-Christian Violet 3, Samantha Grounds 1, Minoo Shakoury-Elizeh 1, Mark Levine 3, Caroline C. Philpott 1
https://doi.org/10.1016/j.tjnut.2023.04.018
Abstract
Background
Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice
lacking a critical liver iron–trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements.
Objectives
We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver.
Methods
C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and
activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet.
Results
The Vit E–fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced
to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2–related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin,
an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05).
Conclusions
Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative
effects of vit E.
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