High-density lipoprotein-facilitated entry of thyroid hormones into cells: a mechanism different from the low-density lipoprotein-facilitated entry.

In human skin fibroblasts incubated with interstitial fluid concentrations of low-density lipoproteins (LDL) (22 microg/mL) that had been preincubated with [(125)I] thyroid hormone (TH), thyroxine (T(4)) whole-cell saturable up-take (CSU) is approximately 40% greater than in control fibroblasts. This effect of the LDL, which requires upregulation of low-density lipoprotein-receptors (LDL-R; K(d) approximately 20 microg/mL), is less for [(125)I]triiodothyronine (T(3)). We have evaluated high-density lipoproteins (HDL), and assessed whether lipoproteins target TH to the nucleus. In some experiments, fibroblasts were cholesterol-deprived (chol(-)) or cholesterol-enriched (chol(+)) to upregulate LDL-R or high-density lipoprotein-receptors (HDL-R), respectively. In chol(-) fibroblasts, 25 microg/mL of LDL increased both T(4) CSU and T(4) nuclear saturable uptake (NSU) by 48% or 30%, respectively; the latter becoming appreciable at approximately 180 minutes. Interstitial fluid concentrations of HDL (280 microg/mL or approximately 50-fold greater than K(d) of the HDL-R) inhibited both T(4) and T(3) CSU even in chol(+) fibroblasts. However, when chol(+) fibroblasts were incubated first with HDL, and after cell washings with [(125)I]T(4) or [(125)I]T(3), T(4) or T(3) CSU increased by 24% or 12%, respectively. The corresponding increase in chol(-) fibroblasts was 8% or 0%, and in nonmanipulated fibroblasts was 15% or 4%. Unlike LDL, the magnitude of the increase in T(4) or T(3) NSU caused by HDL matched the corresponding CSU, and was already evident at 30 minutes. In conclusion, cells have a LDL-facilitated, LDL-R-mediated mode of entry of TH (T(4) >> T(3)) that targets relatively late only part of TH to the nucleus, and an HDL-facilitated mode of entry (T(4) > T(3)) that targets immediately to the nucleus all of the TH, suggesting entry of TH in free form. This effect of HDL represents facilitated diffusion of TH through the cell membrane.