Mice hypomorphic for Keap1, a negative regulator of the Nrf2 antioxidant response, show age-dependent diffuse goiter with elevated thyrotropin levels.

Details

Serval ID
serval:BIB_62561B304595
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mice hypomorphic for Keap1, a negative regulator of the Nrf2 antioxidant response, show age-dependent diffuse goiter with elevated thyrotropin levels.
Journal
Thyroid
Author(s)
Ziros P.G., Renaud C.O., Chartoumpekis D.V., Bongiovanni M., Habeos I., Liao X.H., Refetoff S., Kopp P.A., Brix K., Sykiotis G.P.
ISSN
1557-9077 (Electronic)
ISSN-L
1050-7256
Publication state
Published
Issued date
21/07/2020
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
<b>Background</b>: Familial non-toxic multinodular goiter (MNG) is a rare disease. One of the associated genes is <i>KEAP1</i> (Kelch-like ECH-associated protein 1), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of <i>KEAP1</i> with familial MNG is based on only two loss-of-function mutations identified in two families, only one of which included proper phenotyping and adequate demonstration of co-segregation of the phenotype and the mutation. There is no experimental evidence from model organisms to support that decreased Keap1 levels can indeed cause goiter. The present study used mice hypomorphic for Keap1 to test whether decreased Keap1 expression can cause goiter, and to characterize the activation status of Nrf2 in their thyroid. <b>Methods</b>: C57BL/6J <i>Keap1<sup>flox/flox</sup></i> (Keap1 knock-down; Keap1<sup>KD</sup>) mice were studied at 3 and 12 months of age. Plasma and thyroid glands were harvested for evaluation of thyroid function tests and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. <b>Results</b>: Keap1<sup>KD</sup> mice showed diffuse goiter that began to develop in early adult life and became highly prominent and penetrant with age. The goiter was characterized by a markedly increased size of thyroid follicles, most notably of the colloid compartment, and by absence of thyroid nodules or hyperplasia. Keap1<sup>KD</sup> mice also showed decreased T4 levels in early adult life that were eventually well-compensated over time by increased TSH levels. Nrf2 was activated in the thyroid of Keap1<sup>KD</sup> mice. Despite a known stimulatory effect of Nrf2 on thyroglobulin (Tg) gene transcription and Tg protein abundance, their expression levels were decreased in the thyroid of Keap1<sup>KD</sup> mice. No clear patterns were observed in the expression profiles of other thyroid hormone synthesis-specific factors, with the exception of Tg-processing and Tg-degrading cathepsins, including an increase in mature forms of cathepsins D, L and S. <b>Conclusions</b>: Keap1<sup>KD</sup> mice develop age-dependent diffuse goiter with elevated TSH levels. The precise mechanism accounting for the thyroidal phenotype remains to be elucidated, but it may involve enhanced Tg solubilization and excessive lysosomal Tg degradation.
Pubmed
Create date
24/07/2020 13:01
Last modification date
28/12/2020 6:26
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