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 μg/mL) that had been preincubated with [ 125I] thyroid hormone (TH), thyroxine (T 4) whole-cell saturable uptake (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 ≈ 20 μg/mL), is less for [ 125I]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 μg/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 μg/mL or ≈ 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 [ 125I]T 4 or [ 125I]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.