Thyroid Research Thyroid Research Archive Thyroid Hormone Secretion

Megalin facilitates thyroid hormone secretion by removing thyroid hormone–poor thyroglobulin

(March 2004)

The background of the study. Thyroglobulin, located in the lumen of thyroid follicles, is the site of both synthesis and storage of thyroxine (T4) and triiodothyronine (T3). It enters thyroid cells from the lumen in two ways. One is by the formation of droplets that are taken into thyroid cells and then broken down to release T4 and T3. The other is by binding to megalin, a protein located in the membrane of the cells. The megalin–thyroglobulin complex is carried across the cell to the basal membrane, where the thyroglobulin is released. This study determined whether the hormonal content of thyroglobulin affects its uptake by megalin.

How the study was done and the results. More rat thyroglobulin (Tg) containing no T4 and T3 (hormone-poor Tg) was taken up by and passed through rat thyroid cells grown on a filter to a lower chamber than was Tg containing T4 and T3 (hormone-rich Tg), and the increase was blocked when anti-megalin antibodies were added. Addition of hormone-rich Tg to the cells resulted in the appearance of some T3 in the lower chamber, indicative of breakdown of Tg. Concurrent addition of anti-megalin antibodies increased the content of T3 in the lower chamber, indicating more breakdown of hormone-rich Tg despite the inhibition of megalin-mediated uptake of Tg.

In rats given a drug to inhibit T4 and T3 synthesis and T4 to prevent hypothyroidism, the thyroidal content and distribution of megalin, as determined by immunofluorescence, was similar to that in control rats. Serum Tg concentrations were higher in the treated rats. Anti-Tg antibodies precipitated serum Tg in both groups, but anti-megalin antibodies precipitated serum Tg only in the treated rats, presumably because some of the Tg in the circulation in these rats was megalin-bound.

The conclusions of the study. The megalin pathway of thyroglobulin metabolism in the thyroid gland serves to remove hormone-poor thyroglobulin from the gland, and therefore increase breakdown of hormone-rich thyroglobulin.

The original article. Lisi S, Pinchera A, McCluskey RT, Willnow TE, Refetoff S, Marcocci C, Vitti P, Menconi F, Grasso L, Luchetti F, Collins AB, Marino M. Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release. Proc Natl Acad Sci USA 2003;100:14858-63.