Mice Hypomorphic for Keap1, a Negative Regulator of the Nrf2 Antioxidant Response, Show Age-Dependent Diffuse Goiter with Elevated Thyrotropin Levels.
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State: Public
Version: Final published version
License: CC BY-NC 4.0
State: Public
Version: Final published version
License: CC BY-NC 4.0
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
ISSN
1557-9077 (Electronic)
ISSN-L
1050-7256
Publication state
Published
Issued date
01/2021
Peer-reviewed
Oui
Volume
31
Number
1
Pages
23-35
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Background: Familial nontoxic multinodular goiter (MNG) is a rare disease. One of the associated genes is Kelch-like ECH-associated protein 1 (KEAP1), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of KEAP1 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. This 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. Methods: C57BL/6J Keap1 <sup>flox/flox</sup> (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 for gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Results: 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 thyrotropin (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, the 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. Conclusions: 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.
Keywords
Age Factors, Animals, Biomarkers/blood, Genetic Predisposition to Disease, Goiter, Nodular/blood, Goiter, Nodular/genetics, Goiter, Nodular/pathology, Kelch-Like ECH-Associated Protein 1/deficiency, Kelch-Like ECH-Associated Protein 1/genetics, Male, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2/genetics, NF-E2-Related Factor 2/metabolism, Oxidative Stress, Phenotype, Thyroglobulin/metabolism, Thyroid Gland/metabolism, Thyroid Gland/pathology, Thyrotropin/blood, Up-Regulation, Keap1 hypomorphism, Nfe2l2, cathepsin, oxidative stress, thyroglobulin, thyroid
Pubmed
Web of science
Open Access
Yes
Create date
24/07/2020 14:01
Last modification date
03/10/2023 22:40