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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:359.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor Agonist

Dennis L. Sprecher; Christine Massien; Greg Pearce; Andrew N. Billin; Itay Perlstein; Timothy M. Willson; David G. Hassall; Nicolas Ancellin; Scott D. Patterson; David C. Lobe; Tony G. Johnson

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.

Correspondence to Dennis L. Sprecher, MD, GlaxoSmithKline, Department of Discovery Medicine – Dyslipidemia, 709 Swedeland Road, UW2301, King of Prussia, PA 19406. 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.

A specific PPAR agonist was administered to human volunteers for the first time, revealing a decline in serum TG, an improvement in TG-clearance post-fat feeding, and an elevation in HDLc compared with placebo. Consistent with these findings, in vitro PPAR-treated human skeletal muscle cells induced fatty acid oxidation, and upregulated ABCA1 expression.

Key Words: lipid • PPAR • cholesterol • triglyceride

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