on November 16, 2006
Published online before print November 16, 2006, doi: 10.1161/01.ATV.0000252790.70572.0c
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Submitted on June 26, 2006
Accepted on October 11, 2006
Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor 
Agonist
Dennis L. Sprecher *;
From the Department of Discovery Medicine (D.L.S., C.M., G.P., T.G.J.), Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pa; the Department of High-throughput Biology (A.N.B.), GlaxoSmithKline, Research Triangle Park, NC; the Department of Clinical Pharmacokinetics (I.P.), Modeling and Simulations, GlaxoSmithKline, King of Prussia, Pa; the Department of High Throughput Chemistry (T.M.W.), GlaxoSmithKline, Research Triangle Park, NC; the Department of Safety Assessment (D.G.H.), GlaxoSmithKline, Ware, UK; the Cardiovascular and Urogenital Center of Excellence in Drug Discovery (N.A.), GlaxoSmithKline, Les Ulis, France; the Department of Biomedical Data Sciences (S.D.P.), GlaxoSmithKline, Upper Providence, Pa; and the Department of Metabolic Diseases (D.C.L.), Metabolic and Viral Diseases Center of Excellence in Drug Discovery, GlaxoSmithKline, Research Triangle Park, NC.
* To whom correspondence should be addressed. E-mail: dennis.l.sprecher{at}gsk.com.
Objectives--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)
expression. In parallel, PPAR 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.
Methods and Results--Healthy volunteers were allocated placebo (n=6) or PPAR 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 PPAR 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.
Key words: lipid • PPAR • cholesterol • triglyceride
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