Cholesteryl ester transfer protein (CETP) inhibitors increase high density lipoprotein-cholesterol (HDL-C) in animals and humans, but whether CETP inhibition will be antiatherogenic is still uncertain. We tested the CETP inhibitor torcetrapib in rabbits fed an atherogenic diet at a dose sufficient to increase HDL-C by at least 3-fold (207 6 32 vs. 57 6 6 mg/dl in controls at 16 weeks). CETP activity was inhibited by 70-80% throughout the study. Non-HDL-C increased in both groups, but there was no difference apparent by the study's end. At 16 weeks, aortic atherosclerosis was 60% lower in torcetrapib-treated animals (16.4 6 3.4% vs. 39.8 6 5.4% in controls) and aortic cholesterol content was reduced proportionally. Sera from a separate group of rabbits administered torcetrapib effluxed 48% more cholesterol from Fu5AH cells than did sera from control animals, possibly explaining the reduced aortic cholesterol content. Regression analyses indicated that lesion area in the torcetrapib-treated group was strongly correlated with the ratio of total plasma cholesterol to HDL-C but not with changes in other lipid or lipoprotein levels. CETP inhibition with torcetrapib retards atherosclerosis in rabbits, and the reduced lesion area is associated with increased levels of HDL-C. High levels of high density lipoprotein-cholesterol (HDL-C) have been associated with a decreased incidence of coronary heart disease in epidemiological studies (1-3), and HDL has a number of potentially antiatherogenic properties that may account for its atheroprotective effects.HDL is a key mediator of reverse cholesterol transport, the process by which excess peripheral tissue cholesterol is shunted back to the liver. However, HDL has antiinflammatory (4, 5), antioxidative (6, 7), and antithrombotic activities (8, 9) that may also contribute to its antiatherogenic effects. Because our understanding of exactly how HDL protects against atherosclerosis is not complete, and because HDL speciation, metabolism, and function are complex, perhaps not all mechanisms for increasing HDL-C will ultimately be shown to have equivalent effects on the atherosclerotic process. One HDL-increasing target that has already triggered debate in this regard is cholesteryl ester transfer protein (CETP).CETP is a plasma glycoprotein that transfers cholesteryl esters (CEs), triglycerides, and phospholipids among circulating lipoproteins (10, 11). CETP transfers neutral lipids down concentration gradients; as such, the physiologically relevant direction of the transfer of CE is from the CE-enriched HDL fraction to non-HDL lipoproteins, with retrograde transfer of triglycerides. In the context of reverse cholesterol transport, the transfer of CE via CETP can divert HDL-CE from the direct, hepatic, specific uptake pathway to an indirect pathway for hepatic CE delivery involving the receptor-mediated uptake of apolipoprotein B (apoB)-containing lipoproteins. Under conditions in which hepatic apoB uptake is downregulated, CETP action results in a CE enrichment of non-H...
