title: Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome.
abstract: 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).
  
  
  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.
authors.affiliation: Departments of Pharmacology, University of Pennsylvania, 652 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA. jsmillar@mail.med.upenn.edu
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Danielle
authors.initials: D
authors.lastname: Duffy
authors.forename: Ramprasad
authors.initials: R
authors.lastname: Gadi
authors.forename: LeAnne T
authors.initials: LT
authors.lastname: Bloedon
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dunbar
authors.forename: Megan L
authors.initials: ML
authors.lastname: Wolfe
authors.forename: Rajesh
authors.initials: R
authors.lastname: Movva
authors.forename: Ashish
authors.initials: A
authors.lastname: Shah
authors.forename: Ilia V
authors.initials: IV
authors.lastname: Fuki
authors.forename: Mary
authors.initials: M
authors.lastname: McCoy
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Harris
authors.forename: Ming-Dauh
authors.initials: MD
authors.lastname: Wang
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Howey
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D003903:Deuterium; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood*; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists*; D010919:Placebos; D011422:Propionates / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; C479889:LY 518674; D047493:PPAR alpha; D010919:Placebos; D011422:Propionates; D014230:Triazoles; D014280:Triglycerides; D003903:Deuterium