INHIBITION OF CHOLESTERYL ESTER TRANSFER PROTEIN IN NORMOCHOLESTEROLEMIC AND HYPERCHOLESTEROLEMIC HAMSTERS - EFFECTS ON HDL SUBSPECIES, QUANTITY, AND APOLIPOPROTEIN DISTRIBUTION

The effects of cholesteryl ester transfer protein (CETP) inhibition on the serum lipoprotein profile in both normocholesterolemic and hyperc holesterolemic hamsters has been determined following subcutaneous inj ection of 12.5 mg/kg of the CETP neutralizing monoclonal antibody, TP2 . Inhibition of CETP activity was greater than 60% and resulted in a 3 0-40% increase in high density lipoprotein (HDL) in both normal and hy percholesterolemic animals. These HDL effects were observed 1 day post -injection, were maximal by 4 days, and returned to control values by 14 days. Inhibition of CETP activity resulted in a decrease in both lo w density lipoprotein (LDL) and very low density lipoprotein (VLDL) ch olesterol concomitant with HDL increase, and in hypercholesterolemic a nimals resulted in increased total serum cholesterol. In addition to t he quantitative differences in LDL and HDL, there were significant inc reases in the size of the HDL, a shift to smaller LDL particles, and c hanges in apolipoprotein (ape) composition as evaluated by FPLC and We stern blot analysis. Large apoA-I-poor and apoE-containing HDL became prevalent in hypercholesterolemic hamsters after CETP inhibition. In a ddition, the size of the CETP-containing HDL particles increased with inhibition of transfer activity. While these effects were apparent in normocholesterolemic animals, the changes in apolipoprotein distributi on and HDL subspecies as detected on native gels were more significant in the hypercholesterolemic animals. The changes in the HDL profile a nd apolipoprotein distribution after CETP inhibition in hamsters were similar to those reported in CETP-deficient Japanese subjects, suggest ing the utility of the hypercholesterolemic hamster as an in vivo mode l for the understanding of the lipoprotein changes associated with CET P inhibition.