Pioglitazone, a PPARγ Agonist, Upregulates the Expression of Caveolin-1 and Catalase, Essential for Thyroid Cell Homeostasis: A Clue to the Pathogenesis of Hashimoto's Thyroiditis.
Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that regulates the expression of multiple target genes involved in several metabolic pathways as well as in inflammation. The expression and cell localization of caveolin-1 (Cav-1), thyroperoxidase (TPO), and dual oxidase (DUOX), involved in extracellular iodination, is modulated by Th1 cytokines in human normal thyroid cells and in Hashimoto's thyroiditis (HT).



The objectives of this study were (i) to analyze the PPARγ protein and mRNA expression at the follicular level in HT versus controls in correlation with the one of Cav-1; (ii) to study the effects of Th1 cytokines on PPARγ and catalase expression in human thyrocyte primary cultures; and (iii) to study the effects of pioglitazone, a PPARγ agonist, on thyroxisome components (Cav-1, TPO, DUOX) and on catalase, involved in antioxidant defense.



Although the global expression of PPARγ in the whole gland of patients with HT was not modified compared with controls, there was great heterogeneity among glands and among follicles within the same thyroid. Besides normal (type 1) follicles, there were around inflammatory zones, hyperactive (type 2) follicles with high PPARγ and Cav-1 expression, and inactive (type 3) follicles which were unable to form thyroxine and did not express PPARγ or Cav-1. In human thyrocytes in primary culture, Th1 cytokines decreased PPARγ and catalase expression; pioglitazone increased Cav-1, TPO, and catalase expression.



PPARγ may play a central role in normal thyroid physiology by upregulating Cav-1, essential for the organization of the thyroxisome and extracellular iodination. By upregulating catalase, PPARγ may also contribute to cell homeostasis. The inhibitory effect of Th1 cytokines on PPARγ expression may be considered as a new pathogenetic mechanism for HT, and the use of PPARγ agonists could open a new therapeutic approach.
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Alexis
A
Werion
2 de Pharmacologie et Thérapeutique, et, Université Catholique de Louvain , Brussels, Belgium .
Virginie
V
Joris
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Michael
M
Hepp
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Lida
L
Papasokrati
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Lancelot
L
Marique
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Christine
C
de Ville de Goyet
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Victoria
V
Van Regemorter
3 de Chirurgie, et, Université Catholique de Louvain , Brussels, Belgium .
Michel
M
Mourad
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Benoit
B
Lengelé
4 Départements d'Endocrinologie, Université Catholique de Louvain , Brussels, Belgium .
Chantal
C
Daumerie
5 d'Anatomo-pathologie, Secteur des Sciences de la Santé, Faculté de Médecine, Université Catholique de Louvain , Brussels, Belgium .
Etienne
E
Marbaix
4 Départements d'Endocrinologie, Université Catholique de Louvain , Brussels, Belgium .|6 d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain , Brussels, Belgium .
Sonia
S
Brichard
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Marie-Christine
MC
Many
1 Pôles de Morphologie, Université Catholique de Louvain , Brussels, Belgium .
Julie
J
Craps
D001324:Autoantigens / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D000074623:Dual Oxidases / Q000378:metabolism; D050031:Hashimoto Disease / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007453:Iodide Peroxidase / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000072637:Thyroid Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D001324:Autoantigens; D051242:Caveolin 1; D007004:Hypoglycemic Agents; D033862:Iron-Binding Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000074623:Dual Oxidases; D002374:Catalase; C056658:TPO protein, human; D007453:Iodide Peroxidase; C431513:DUOX1 protein, human; D000077205:Pioglitazone