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

Abstract

Amiodarone, a potent antiarrhythmic drug, decreases plasma and tissue triidothyronine (T 3) and increases plasma cholesterol levels, resembling changes seen during hypothyroidism. The increase of serum cholesterol during amiodarone medication is associated with a decreased expressionof 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 (K d). In conclusion, amiodarone-induced hypercholesterolemia can be explained by decreased transcription of the LDL receptor gene, resulting in lower mRNA and protein levels.