Amiodarone decreases gene expression of low-density lipoprotein receptor at both the mRNA and the protein level.

Amiodarone, a potent antiarrhythmic drug, decreases plasma and tissue triiodothyronine (T3) and increases plasma cholesterol levels, resembling changes seen during hypothyroidism. The increase of serum cholesterol during amiodarone medication is associated with a decreased expression of the hepatic low-density lipoprotein (LDL) receptor mRNA. To further elucidate the mechanism of amiodarone-induced hypercholesterolemia, we investigated whether the decreased mRNA levels are the result of decreased transcription or increased degradation or both, and whether protein expression is decreased accordingly. Relative to pair-fed controls, amiodarone treatment increased plasma cholesterol by 69% and decreased expression of the mRNA encoding for the hepatic LDL receptor by 45%. To study this decrease in mRNA, we performed a run-on assay, from which it appears that amiodarone acts by decreasing LDL receptor mRNA expression 2.5-fold at the transcriptional level. The decay rate of liver LDL receptor mRNA, measured at different time points after injecting actinomycin D, was not different between amiodarone-treated and control animals (116+/-32 minutes and 84+/-10 minutes, P=.44). Hepatocytes in primary culture isolated from amiodarone-treated and control animals were used to determine specific binding of [125I]-LDL to hepatic LDL receptors. Amiodarone decreased specific LDL binding and Scatchard analysis demonstrated that amiodarone treatment reduced the number of LDL receptors by 69%, without affecting the dissociation constant (Kd). In conclusion, amiodarone-induced hypercholesterolemia can be explained by decreased transcription of the LDL receptor gene, resulting in lower mRNA and protein levels.