Paracrine interaction between hepatocytes and macrophages after extrathyroidal proteolysis of thyroglobulin.

Thyroglobulin (Tg), the precursor of the thyroid hormones triiodothyronine (T3) and thyroxine (T4), is known to derive from thyroid epithelial cells. Part of Tg reaches the circulation as an intact molecule by transcytosis across the epithelial wall of thyroid follicles. Circulating Tg is a potential ligand for the asialoglycoprotein receptor of hepatocytes. In this report we show, however, that clearance of circulating Tg occurred exclusively by endocytosis in liver macrophages, whereas hepatocytes did not participate in this process. The biological significance of this Tg uptake by the macrophages might consist in an increase of thyroid hormones in close proximity to the macrophages, thereby affecting the hepatocyte metabolism. To test this hypothesis, co-cultures of hepatocytes and macrophages were incubated with Tg, which resulted in the release of thyroid hormones and in a significant increase in the activity of lipogenesis and of hepatocellular key enzymes of the hexose monophosphate shunt. This effect of Tg could be mimicked by equivalent amounts of T3 or T4 exclusively in the co-cultures. When hepatocytes were incubated with thyroid hormones in the absence of macrophages, no or only little effect was observed, indicating that the interaction of macrophages and hepatocytes was a prerequisite for the stimulation of the hepatocellular metabolism. We conclude that the paracrine effect on HepG2 cells results from the degradation of Tg in J774 cells. Apparently, this process is not confined to the release of thyroid hormones, but it requires the interaction of both cell types, possibly mediated by an additional, as yet unknown stimulus.