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Thyroid Hormone Efflux from Monolayer Cultures of Human Fibroblasts and Hepatocytes. Effect of Lipoproteins and Other Thyroxine Transport Proteins

Cattedra and Servizio Autonomo di Endocrinologia, University of Messina, School of Medicine, 98125 Messina, Italy, and Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1587

Address all correspondence and requests for reprints to: Jacob Robbins, M.D., NIDDK, Genetics and Biochemistry Branch, Building 10, Room 6C 201A, 10 Center Drive, MSC 1587, Bethesda, Maryland 20892-1587.

We have previously shown that human skin fibroblasts exposed to preformed low density lipoprotein (LDL)-thyroxine (T₄) complexes internalize more T₄ than they do when exposed to T₄ alone. The system is set to function when the LDL receptor is up-regulated by reducing the intracellular concentration of cholesterol, and the LDL concentration outside the cell is in the range of the kDa of the receptor. High density lipoproteins (HDL), albumin (HSA), transthyretin (TTR), and thyroxine-binding globulin (TBG) interfere with, rather than facilitate, T₄ entry.

Of the three classes of lipoproteins (VLDL, LDL, and HDL), HDL is the major carrier of thyroid hormones. While LDL delivers cholesterol (and T₄) to cells, HDL is the scavenger of cholesterol. We thus hypothesized that HDL could also facilitate thyroid hormone exit from cells. This hypothesis was tested on two human cell lines: skin fibroblasts and hepatocytes (Hep G2), using physiological concentrations of HDL or, as control, physiological concentrations of LDL, HSA, TTR, and TBG or buffer. Because cell surface receptors for HDL are regulated by intracellular cholesterol in a manner opposite to that of LDL receptors, we evaluated the effect of HDL (and other proteins) in three states: normal, high, and low intracellular cholesterol content (i.e. normal, high, and low expression of HDL receptors).

In both cell lines and with either T₄ or T₃, we found that: 1) HDL as well as the other proteins tested increased the efflux and augmented both the initial rate of exit and the equilibrium value. 2) The efflux did not saturate over a wide range of protein concentrations. 3) The effect of HDL, LDL, and the other proteins on the fractional efflux rate of thyroid hormones remained the same irrespective of the intracellular cholesterol content (and, therefore, irrespective of the expression of either LDL or HDL receptors). 4) HSA, TTR, and TBG were, on a mass basis, equipotent and more efficient than lipoproteins. However, the effect of lipoproteins – whose Ka for T₄ is comparable to that of HSA – was disproportionately high. On a molar basis, LDL (about 80% of the weight being accounted for by lipids) was more effective than HDL₂ (about 60% lipids) and HDL₂ was more effective than HDL₃ (about 40% lipids), suggesting that the disproportionate effect of lipoproteins was due to transfer of the lypophylic thyroid hormones to the lipid moiety of lipoproteins. 5. A mixture of HDL and LDL gave the same efflux rate as a mixture of HSA, TTR, and TBG.

The data indicate that the efflux of T₄ and T₃ from cells is rapid and appears not to be mediated by a particular lipoprotein. The disproportionately large effect of lipoproteins, which are low affinity thyroid hormone carriers, compared with nonlipoprotein carriers, and the greater effect of LDL compared with HDL, might indicate that the lipoproteins establish a nonspecific physical contact with the plasma membrane and that their hydrophobic nature favors the release of the similarly hydrophobic thyroid hormones.

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