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Characterization of the Binding of Thyroxine to High Density Lipoproteins and Apolipoproteins A-I

Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, and Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda, Maryland 20892

Address requests for reprints to: Dr. Jacob Robbins, Clinical EndocrinologyBranch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.

We studied binding of T₄ to the lipid-complexed apolipoproteins (apo) of high density lipoproteins (HDL), the major lipoprotein carrier of thyroid hormones in human plasma, and to lipid-free apoA-I. HDL isolated from fresh normal plasma by ultracentrifugation (density, 1.063–1.210 g/mL) was photoaffinity labeled with [3,5–¹²⁶I]T₄ and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two bands corresponding to apoA-I (28.3K) and apoC-II or apoC-III (8.6–9.2K) were seen, and their radioactivity decreased by 50–60% when labeled in the presence of 1 µmol/L T₄. Photoaffinity labeling of isolated apoA-I also was demonstrated and was decreased 74% by 1 µmol/L T₄, suggesting a higher affinity of the lipid-free protein for T₄. T₄ binding of isolated apoA-I was optimal at pH 7–8, reached a maximum after 1 h at 23 C, and decreased after incubation at 37 C. Scatchard analysis revealed a single T₄-binding site with a Ka of 7.5 x 10⁷ L/mol at 23 C, pH 8.2. The potency of T₄ analogs as inhibitors of T₄ binding to isolated apoA-I was L-T₄ = D-T₄ = triiodothyroacetic acid = L-rT3:>> L-T₃ >> L-thyronine. The binding of T₄ to apoA-I was reduced by known inhibitors of T₄ binding to serum proteins (diclofenac = mefenamic acid = furosemide = 8-anilinonaphthalene sulfonic acid >> dilantin > heparin > barbital) and by lipids (unsaturated fatty acids > cholesterol = cholesterol esters = phospholipids > saturated fatty acids = diglycerides = triglycerides). We conclude that the binding of T₄ to HDL is mediated by a specific interaction of the hormone with apoA-I and with apoC-II and/or apoC-III. Since the lipid constituents of HDL inhibit T₄ binding to apoA-I, the HDL subfraction in plasma that carries most of the HDL-bound T₄ should be one with a low lipid content.

^* Supported by a grant from Consiglio Nazionale di Ricerche-NATO (Rome, Italy). Permanent address: Thyroid Unit, Istituto Pluridisciplinare di Clinica Medica e Terapia Medica Generale e Speciale, University of Messina, School of Medicine, 98100 Messina, Italy.

Received October 25, 1988.

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