High Iron Exposure from the Fetal Stage to Adulthood in Mice Alters Lipid Metabolism

Kim, Min-Ju; Kim, Yeonhee; Min, Sohyun; Lee, Seung Min

doi:10.3390/nu14122451

Cited by 3 publications

(1 citation statement)

References 114 publications

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“…However, iron overload (IO) leads to disorder of the iron metabolism. Patients with conditions such as aplastic anemia, myelodysplastic syndrome, sickle-cell disease, as well as transfusion-dependent patients with thalassemia major, have the characteristics of IO, and excessive iron can be cytotoxic, resulting in the inducing of global oxidative damage and lipid peroxidation by generating reactive oxygen species (ROS) [ 6 , 7 , 8 ]. Moreover, iron overload eventually leads to serious chronic consequences including hemorrhagic inflammation, hepatic cirrhosis, diabetes, innate immune dysfunction, as well as growth arrest and cell death [ 1 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

L-Citrulline Supplementation Restrains Ferritinophagy-Mediated Ferroptosis to Alleviate Iron Overload-Induced Thymus Oxidative Damage and Immune Dysfunction

Zhao

Chen

et al. 2022

Nutrients

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L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+ T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells’ viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.

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