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 first ATG of the human LDL receptor gene by co-transfection with TRbeta1 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 T3. 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 TRbeta1 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% T3 alone vs. 380% respectively, p<0.01).
Bakker
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Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
Hudig
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Meijssen
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S
Wiersinga
W M
WM
D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000889:Anti-Arrhythmia Agents; D011973:Receptors, LDL; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; C036116:desethylamiodarone; D000638:Amiodarone