EFFECTS OF TRIIODOTHYRONINE AND AMIODARONE ON THE PROMOTER OF THE HUMAN LDL RECEPTOR GENE

Treatment of patients with amiodarone, a potent anti arrhythmic drug, increases plasma LDL cholesterol levels, similar to that seen during h ypothyroidism. This increase is the result of a decreased expression o f the hepatic LDL receptor gene. We investigated the effects of thyroi d hormone, amiodarone and desethylamiodarone on the first 687 bp upstr eam of the firrst ATG; of the human LDL receptor gene by co-transfecti on with TR beta 1 into HepG2 cells. Promoter activity showed a dose-de pendent increase upon addition of thyroid hormone up to a maximum of 6 00% at 10(-6) M T-3 Using 5'-deletions it was found that a functional TRE(s) is present between -687 bp and -160 bp upstream of the ATG of t he LDL receptor gene. Amiodarone and desethylamiodarone at 10-6 M redu ced basal LDL receptor promoter activity further then with the TR beta 1 alone (to 30% vs. 50% respectively, p < 0.01) but interestingly in combination with T3 these compunds show a synergistic effect on promot er activity (to 225% T-3 alone vs. 380% respectively, p < 0.01). (C) 1 998 Academic Press.