Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.
OBJECTIVE
Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)delta expression. In parallel, PPARdelta agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models.


RESULTS
Healthy volunteers were allocated placebo (n=6) or PPARdelta agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (-11.5+/-1.6%, P=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (P=0.002). However, LpL expression remained unchanged.


CONCLUSIONS
This is the first report of a PPARdelta agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.
Sprecher
Dennis L
DL
GlaxoSmithKline, Department of Discovery Medicine-Dyslipidemia, 709 Swedeland Road, UW2301, King of Prussia, PA 19406, USA. dennis.l.sprecher@gsk.com
Massien
Christine
C
Pearce
Greg
G
Billin
Andrew N
AN
Perlstein
Itay
I
Willson
Timothy M
TM
Hassall
David G
DG
Ancellin
Nicolas
N
Patterson
Scott D
SD
Lobe
David C
DC
Johnson
Tony G
TG
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D005227:Fatty Acids; C425931:GW 501516; D008075:Lipoproteins, HDL; D047494:PPAR delta; D013844:Thiazoles; D014280:Triglycerides