Megalin in thyroid physiology and pathology

Megalin, a member of the low density lipoprotein endocytic receptor family, is expressed on the apical surface of thyroid epithelial cells, directly f acing the follicle lumen, where colloid is stored in high concentrations. S tud ies in vivo and with cultured thyroid cells have provided evidence that megalin expression on thyroid cells is TSH-dependent. Thyroglobulin (Tg), the major protein component of the colloid and the precursor of thyroid hor mones, binds to megalin with high affinity and megalin mediates in part its uptake by thyrocytes. Tg internalized by megalin avoids the lysosomal path way and is delivered by transepithelial transport (transcytosis) to the bas olateral membrane of thyrocytes, from which it is released into the bloodst ream. This process com petes with pathways leading to thyroid hormone relea se from Tg molecules, which occurs following internalization of Tg molecule s from the colloid by other means of uptake (fluid phase endocytosis or end ocytosis mediated by low affinity receptors) that result in proteolytic cle avage in the lyosomes. During transcytosis of Tg, a portion of megalin (sec retory component) remains complexed with Tg and enters the circulation, whe re its detection may serve as a tool to identify the origin of serum Tg in patients with thyroid diseases. Tg endocytosis via megalin is facilitated b y the interaction of Tg with cell surface heparan sulfate proteoglycans, wh ich occurs via a carboxyl terminal heparin binding site of Tg functionally related with a major megalin binding site. Although autoantibodies against megalin can be found in the serum of similar to 50% of patients with autoim mune thyroiditis, a role or megalin in this and other thyroid diseases rema ins to be established.