The NFE2-related transcription factor 2 (Nrf2) coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland.

Related Articles

The NFE2-related transcription factor 2 (Nrf2) coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland.

Thyroid. 2018 May 10;:

Authors: Ziros PG, Habeos I, Chartoumpekis DV, Ntalampyra E, Somm E, Renaud CO, Bongiovanni M, Trougakos IP, Yamamoto M, Kensler TW, Santisteban P, Carrasco N, Ris-Stalpers C, Amendola E, Liao XH, Rossich L, Thomasz L, Juvenal GJ, Refetoff S, Sykiotis GP

Abstract
BACKGROUND: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Although antioxidant and detoxification enzymes presumably aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including under conditions of exposure to excess iodide, the factors that coordinate their expression with the cellular redox status are not known. Across the evolutionary spectrum, the ubiquitously expressed transcription factor NFE2-related transcription factor 2 (Nrf2) is required to defend tissues against oxidative stress, thereby protecting organisms against pathologies that relate to DNA, protein and/or lipid oxidative damage. Thus, we hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis.
METHODS: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were used. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time PCR and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation.
RESULTS: We show here that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, we also found that Nrf2 has a dramatic impact on both the basal abundance and the thyroid stimulating hormone (TSH)-inducible intra-thyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide.
CONCLUSIONS: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.

PMID: 29742982 [PubMed - as supplied by publisher]

https://ift.tt/2jQl2S8