Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome.
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.
Millar
John S
JS
Departments of Pharmacology, University of Pennsylvania, 652 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA. jsmillar@mail.med.upenn.edu
Duffy
Danielle
D
Gadi
Ramprasad
R
Bloedon
LeAnne T
LT
Dunbar
Richard L
RL
Wolfe
Megan L
ML
Movva
Rajesh
R
Shah
Ashish
A
Fuki
Ilia V
IV
McCoy
Mary
M
Harris
Cynthia J
CJ
Wang
Ming-Dauh
MD
Howey
Daniel C
DC
Rader
Daniel J
DJ
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
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