Potent and Selective PPAR- Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome

Objective—The study of PPARactivation on apoA-I production in humans has been limited to fibrates, relatively weak PPARagonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPARagonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). Methods and Results—Subjects were randomized to receive LY518674 (100 g) once daily (n 13) or placebo (n 15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C ( 38%, P 0.002) and triglyceride ( 23%, P 0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 ( 12%, P 0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P 0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P 0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P 0.0001) accompanied by a 25% increase in the FCR (P 0.0001), resulting in a significant increase in plasma apoA-II. Conclusions—Activation of PPARwith LY518674 (100 g) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined. (Arterioscler Thromb Vasc Biol. 2009;29:140-146.)