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 hypothyroidism. This increase is the result of a decreased expression of the hepatic LDL receptor gene. We investigated the effects of thyroid hormone, amiodarone and desethylamiodarone on the first 687 bp upstream of the firrst ATG; of the human LDL receptor gene by co-transfection with TR beta 1 into HepG2 cells. Promoter activity showed a dose-dependent increase upon addition of thyroid hormone up to a maximum of 600% 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 the LDL receptor gene. Amiodarone and desethylamiodarone at 10-6 M reduced 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 promoter activity (to 225% T-3 alone vs. 380% respectively, p < 0.01). (C) 1998 Academic Press.