Changes in plasma lipoprotein cholesterol levels by antisense oligodeoxynucleotides against cholesteryl ester transfer protein in cholesterol-fed rabbits

Abstract

Cholesteryl ester transfer protein (CETP) is the enzyme that facilitates the transfer of cholesteryl ester from high density lipoprotein (HDL) to apoB-containing lipoproteins and also affects the low density lipoprotein metabolism. On the other hand, the liver is the major tissue responsible for the production of CETP (CETP mRNA) in rabbits. To test the hypothesis that a reduction of CETP mRNA in the liver by antisense oligodeoxynucleotides (ODNs) may affect the plasma lipoprotein cholesterol levels, we intravenously injected antisense ODNs against rabbit CETP coupled with asialoglycoprotein carrier molecules, which serve as an important method to regulate liver gene expression, to cholesterol-fed rabbits via their ear veins. All rabbits were fed a standard rabbit chow supplement with 0.1% cholesterol for 10 weeks before and throughout the experiment. After injecting rabbits with antisense ODNs, the plasma total cholesterol concentrations and plasma CETP activities all decreased at 24, 48, and 96 h, whereas the plasma HDL cholesterol concentrations increased at 48 h. A reduction in the hepatic CETP mRNA was also observed at 6, 24, and 48 h after the injection with antisense ODNs. However, in the rabbits injected with sense ODNs, the plasma total and HDL cholesterol concentrations and the plasma CETP activities did not significantly change, and the hepatic CETP mRNA did not change either throughout the experimental period. Although the exact role of CETP in the development of atherosclerosis remains to be clarified, these findings showed for the first time that the intravenous injection with antisense ODNs against CETP coupled to asialoglycoprotein carrier molecules targeted to the liver could thus inhibit plasma CETP activity and, as a result, could induce a decrease in the plasma low density lipoprotein and very low density lipoprotein cholesterol and an increase in the plasma HDL cholesterol in cholesterol-fed rabbits.