title: Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice.
abstract: 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.
authors.affiliation: Department of Endocrinology, University of Pisa, via Paradisa 2, I-56124 Pisa, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Lisi
authors.forename: Roberta
authors.initials: R
authors.lastname: Botta
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinchera
authors.forename: A Bernard
authors.initials: AB
authors.lastname: Collins
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Lucia
authors.initials: L
authors.lastname: Grasso
authors.forename: Vladimir
authors.initials: V
authors.lastname: Marshansky
authors.forename: Shaliha
authors.initials: S
authors.lastname: Bechoua
authors.forename: Andres
authors.initials: A
authors.lastname: Hurtado-Lorenzo
authors.forename: Claudio
authors.initials: C
authors.lastname: Marcocci
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Robert T
authors.initials: RT
authors.lastname: McCluskey
authors.forename: Michele
authors.initials: M
authors.lastname: Marinò
mesh_terms: D000818:Animals; D001692:Biological Transport; D005260:Female; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000378:metabolism; D013954:Thyroglobulin / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism
chemical_list: D026563:LDL-Receptor Related Protein-Associated Protein; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D011973:Receptors, LDL; D013954:Thyroglobulin; D013974:Thyroxine