DOWN-REGULATION OF MESSENGER-RNA FOR THE LOW-DENSITY-LIPOPROTEIN RECEPTOR IN TRANSGENIC MICE CONTAINING THE GENE FOR HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN - MECHANISM TO EXPLAIN ACCUMULATION OF LIPOPROTEIN-B PARTICLES

To evaluate the effects of cholesteryl ester transfer protein (CETP) o n apoB-containing lipoproteins, we analyzed plasma lipoproteins from t hree different lines of human CETP transgenic mice, with plasma CETP c oncentration ranging from low (1.5 mug/ml) to high levels (8.5 mug/ml) . With increasing CETP concentration, very low density lipoprotein and low density lipoprotein (LDL) cholesteryl ester (CE) and apoB were pr ogressively increased, and high density lipoprotein CE was decreased. To investigate the mechanism of accumulation of lipoproteins containin g apoB (lipoprotein B), the abundance of hepatic LDL receptor mRNA was determined. LDL receptor mRNA was reduced as a result of CETP express ion, with maximum repression to about 48% of the level of non-transgen ic mice. Among the different lines of CETP transgenic mice there was a n inverse relationship between plasma CETP concentration and hepatic L DL receptor mRNA abundance (r = -0.94, p < 0.01). CETP expression also led to increased cholesterol and cholesteryl ester content in liver a nd to decreased abundance of mRNAs encoding 3-hydroxy-3-methylglutaryl -coenzyme A reductase and 7-alpha-hydroxylase. Thus, CETP expression r esults in increased cholesteryl ester concentration in very low densit y lipoprotein and LDL, probably reflecting both CE transfer from high density lipoprotein and accumulation of lipoprotein B particles. The a ccumulation of lipoprotein B particles results from CETP-mediated down -regulation of liver LDL receptors, possibly due to enhanced return of cholesterol to the liver.