Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome

Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):140-6. doi: 10.1161/ATVBAHA.108.171223. Epub 2008 Nov 6.


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

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoprotein A-I / blood*
  • Apolipoprotein A-I / genetics
  • Cholesterol, HDL / blood
  • Cholesterol, VLDL / blood
  • Deuterium
  • Double-Blind Method
  • Female
  • Humans
  • Kinetics
  • Male
  • Metabolic Syndrome / blood*
  • Middle Aged
  • PPAR alpha / agonists*
  • Placebos
  • Propionates / pharmacology*
  • Triazoles / pharmacology*
  • Triglycerides / blood
  • Young Adult


  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Cholesterol, VLDL
  • LY 518674
  • PPAR alpha
  • Placebos
  • Propionates
  • Triazoles
  • Triglycerides
  • Deuterium