Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice

• Published in: American Journal of Physiology: Cell Physiology 2006-04, Vol.290 (4), p.C1160-C1167
• Main Authors: Lisi, Simonetta, Botta, Roberta, Pinchera, Aldo, Collins, A. Bernard, Refetoff, Samuel, Arvan, Peter, Bu, Guojun, Grasso, Lucia, Marshansky, Vladimir, Bechoua, Shaliha, Hurtado-Lorenzo, Andres, Marcocci, Claudio, Brown, Dennis, McCluskey, Robert T, Marino, Michele
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Female; Humans; LDL-Receptor Related Protein-Associated Protein - genetics; LDL-Receptor Related Protein-Associated Protein - metabolism; Low Density Lipoprotein Receptor-Related Protein-2 - metabolism; Male; Mice; Mice, Knockout; Receptors, LDL - metabolism; Thyroglobulin - metabolism; Thyroid Gland - cytology; Thyroid Gland - metabolism; Thyroxine - metabolism
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00382.2005

1 Department of Endocrinology, University of Pisa, Pisa, Italy; 2 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; 3 Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois; 4 Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan; 5 Departments of Pediatrics, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, Missouri; and 6 Program in Membrane Biology, Renal Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts Submitted 29 July 2005 ; accepted in final form 16 November 2005 The molecular chaperone receptor-associated protein (RAP) is required for biosynthesis of megalin, an endocytic receptor for follicular thyroglobulin (Tg), the thyroid hormone precursor. RAP also binds to Tg itself, suggesting that it may affect Tg trafficking in various manners. To elucidate RAP function, we have studied the thyroid phenotype in RAP-knockout (RAP-KO) mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with those of wild-type (WT) mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained as indicated by normal serum thyroxine levels. Because Tg in thyroid extracts from RAP-KO mice contained thyroxine residues as in WT mice, we concluded that in RAP-KO mice, follicular Tg, although reduced, was nevertheless sufficient to provide normal hormone secretion. Serum TSH was increased in RAP-KO mice, and although no thyroid enlargement was observed, some histological features resembling early goiter were present. Megalin was decreased in RAP-KO mice, but this did not affect thyroid function, probably because of the concomitant reduction of follicular Tg. In conclusion, RAP is required for the establishment of Tg reservoirs, but its absence does not affect hormone secretion. low-density lipoprotein; knockout mice Address for reprint requests and other correspondence: M. Marinò, Dept. of Endocrinology, Univ. of Pisa, via Paradisa 2, I-56124 Pisa, Italy (e-mail: m.marino{at}endoc.med.unipi.it )