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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:140.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

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

John S. Millar; Danielle Duffy; Ramprasad Gadi; LeAnne T. Bloedon; Richard L. Dunbar; Megan L. Wolfe; Rajesh Movva; Ashish Shah; Ilia V. Fuki; Mary McCoy; Cynthia J. Harris; Ming-Dauh Wang; Daniel C. Howey; Daniel J. Rader

From the Departments of Pharmacology (J.S.M.) and Medicine (D.D., R.G., L.T.B., R.L.D., M.L.W., A.S., I.V.F., M.M., D.J.R.), Institute for Translational Research and Therapeutics, University of Pennsylvania, Philadelphia; Pennsylvania Hospital (R.M.), Philadelphia; and Eli Lilly and Company (C.J.H., M.-D.W., D.C.H.), Indianapolis, Ind.

Correspondence to John S. Millar, PhD, University of Pennsylvania, 652 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail jsmillar{at}mail.med.upenn.edu

Objective— The study of PPAR- activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR- agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR- agonist, 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 µg) 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 PPAR- with LY518674 (100 µg) 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.

We studied apoA-I and apoA-II metabolism after treatment with a potent and specific PPAR- agonist, LY518674, or placebo for 8 weeks. LY518674 increased apoA-I and apoA-II production and fractional catabolic rates leaving HDL-C levels unchanged. LY518674 significantly increases apoA-I production and clearance despite no change in HDL.

Key Words: apolipoproteins • cardiovascular disease prevention • hyperlipoproteinemia • lipoproteins