Unesterified long‐chain fatty acids inhibit thyroid hormone binding to the nuclear receptor

Abstract

Unesterified long-chain fatty acids strongly inhibited thyroid hormone (T₃) binding to nuclear receptors extracted from rat liver, kidney, spleen, brain, testis and heart. Oleic acid was the most potent inhibitor, attaining 50% inhibition at 2.8 μM. Oleic acid similarly inhibited the partially purified receptor and enhanced dissociation of the preformed T₃-receptor complex. The fatty acid acted in a soluble form and in a competitive manner for the T₃-binding sites, thereby reducing the affinity of the receptor for T₃. The affinity of the receptor for oleic acid (K_i) was 1.0 μM. In HTC rat hepatoma cells in culture, fatty acids added to the medium reached the nucleus and inhibited nuclear T₃ binding; oleic acid being the most potent. T₃ binding of the cells was reversibly restored in fresh medium free of added fatty acids. Oleic acid did not affect all the T₃-binding sites in the HTC cells: one form (80%) was inhibited and the other was not and these two forms were commonly present in all rat tissues examined. Thus, fatty acids inhibited the solubilized nuclear receptor as well as a class of nuclear T₃-binding sites in cells in culture.