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.
Highlights
Almost all enzymes and apolipoproteins are produced in the liver; the efficient receptor-mediated delivery of antisense ODNs to the liver in vivo used in our study may be useful for both diagnostic and therapeutic applications for lipoprotein metabolism
The assay used for the Cholesteryl ester transfer protein (CETP) activity in this study cannot always show the true CE mass transfer in vivo, because the assay uses exogenous lipoprotein substrates added in the assay, whereas in vivo the CE is transferred among the endogenous lipoproteins of plasma [25]
It is indicated that the reduction of plasma CETP reduces the plasma levels of LDL and VLDL cholesterol possibly by enhancing LDL catabolism [7] and possibly by decreasing the transfer of cholesteryl ester from high density lipoprotein (HDL) to apoBcontaining lipoproteins [1, 2], and it increases the plasma level of HDL cholesterol, possibly due to the latter reason
Summary
CETP-deficient subjects have been found to have a substantially increased catabolic rate of apoB as the primary metabolic basis for the low plasma levels of LDL apo B [7]. The present study was undertaken to determine the effect of an intravenous injection with antisense ODNs to the liver on the CETP mRNA expression, plasma CETP activity and plasma cholesterol concentrations in rabbits fed a low cholesterol diet. These antisense ODNs were originally designed to be coupled with asialoglycoprotein carrier molecules, and this coupling serves as an important method to regulate liver gene expression [13]. CETP deficiency in humans [3,4,5] has been proposed to be associated with longevity
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