NDLI: Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release.

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Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release.

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Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lisi, Simonetta Collins, A. Bernard Vitti, Paolo Pinchera, Aldo Marcocci, Claudio Willnow, Thomas E. Marino, Michele Luchetti, Fabiana Menconi, Francesca Mccluskey, Robert T. Grasso, Lucia Refetoff, Samuel
Description	Author Affiliation: Lisi S ( Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy.);
Abstract	Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Low Density Lipoprotein Receptor-Related Protein-2 Chemistry Thyroglobulin Metabolism Thyroid Hormones Amitrole Pharmacology Animals Dose-Response Relationship, Drug Endocytosis Enzyme-Linked Immunosorbent Assay Graves Disease Heparitin Sulfate Homozygote Hormones Hypothyroidism Methimazole Mice Mice, Transgenic Models, Biological Precipitin Tests Rats, Inbred Lew Blood Thyroid Gland Physiology Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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