|Diffenderfer, Margaret R.|
|Brousseau, Margaret E.|
|Millar, John S.|
|Barrett, P. Hugh R.|
|Schaefer, Peter M.|
|Wolfe, Megan L.|
|Dolnikowski, Gregory G.|
|Rader, Daniel J.|
|Schaefer, Ernst J.|
Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2012
Publication Date: 6/1/2012
Citation: Diffenderfer, M., Brousseau, M., Millar, J., Barrett, P., Nartsupha, C., Schaefer, P., Wolfe, M., Dolnikowski, G., Rader, D., Schaefer, E. 2012. Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism. Journal of Lipid Research. 53(6):1190-1199. Interpretive Summary: Cholesteryl ester transfer protein (CETP) is a protein in the blood that transfers cholesteryl ester in HDL (also known as good-cholesterol) for triglyceride in other lipoprotein particles (protein-lipid complexes). Inhibition of CETP activity has been shown to increase HDL cholesterol levels and decrease triglyceride levels significantly and, hence, has potential therapeutic benefit in reducing the risk of coronary heart disease. The way in which CETP inhibition alters elevated levels of fat and cholesterol secreted by the intestine after a meal is not known. We studied the in vivo mechanism of the effects of CETP inhibition on the rate of production and clearance of apoB-48, the major protein component of intestinal lipoprotein particles in 18 people with low HDL cholesterol levels, 9 of whom had normal LDL cholesterol levels and 9 of whom received statin therapy in order to achieve normal LDL cholesterol levels. Our study indicates that treatment with a CETP inhibitor reduces cholesteryl ester concentrations in triglyceride-rich lipoproteins by 70%. It also causes a 50% reduction in plasma apoB-48 levels, due to a decrease in the production of apoB-48 by the intestine. In the subjects receiving statin therapy, we found that plasma levels of apoB-48 are already reduced by statin therapy and do not change when CETP activity is inhibited. Our data indicate that CETP inhibition causes beneficial changes in plasma lipoprotein levels: in particular, CETP inhibition is associated with significant decreases in the levels and production of intestinal lipoproteins.
Technical Abstract: Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester (CE) to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (less than40 mg/dl), either untreated (n=9) or receiving atorvastatin 20 mg daily (n=9), received placebo for 4 weeks, followed by torcetrapib 120 mg once-daily for the next 4 weeks. A subset of the subjects not treated with atorvastatin participated in a third phase (n=6), in which they received torcetrapib 120 mg twice-daily for an additional 4 weeks. At the end of each phase, all subjects received a primed-constant infusion of L-leucine, while in the constantly fed state, to determine the kinetics of TRL apoB-48 and TRL composition. Relative to placebo, torcetrapib markedly reduced TRL CE levels in all groups (greater than or equal to -69%; P less than 0.005). ApoB-48 pool size (PS) and production rate (PR) decreased in the non-atorvastatin once- (PS: -49%, P=0.007; PR: -49%, P=0.005) and twice- (PS: -30%, P=0.01; PR: -27%, P=0.13) daily cohorts. In the atorvastatin cohort, apoB-48 PS and PR, which were already lowered by atorvastatin, did not change with torcetrapib. Our findings indicate that CETP inhibition reduced plasma apoB-48 concentrations by reducing apoB-48 production, but did not have this effect in subjects already treated with atorvastatin.