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

Abstract

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 (nϭ6) or PPAR␦ agonist (GW501516) at 2.5 mg (nϭ9) or 10 mg (nϭ9), 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 (Pϭ0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (Pϭ0.02). HDLc was enhanced in both treatment groups (2.5 mg Pϭ0.004, 10 mg PϽ0.001) when compared with the decrease in the placebo group (Ϫ11.5Ϯ1.6%, Pϭ0.002). 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 (Pϭ0.002). However, LpL expression remained unchanged. Conclusions-This is the first report of a PPAR␦ agonist administered to man. In this small study, GW501516 significantly

Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

“…There was also a striking reduction of fasting plasma NEFA, which was seen in the context of increased relative incorporation of labeled CO 2 originating from the fat content in the experimental meal, suggesting increased fat oxidation. The pattern of change in mRNA content in skeletal muscle suggested that pathways for fat oxidation, in both fast and slow fiber types, were specifically upregulated in response to the PPAR␦ drug, which is in line with observations from studies in rodents and human cells (32). Importantly, the increased fat oxidation was seen without any signs of deterioration of glucose/insulin homeostasis.…”

“…PPAR␦ knockout mice appear to be insulin resistant (31). A recent report showed that GW501516 given to lean healthy subjects during metabolic ward conditions for 2 weeks resulted in a modest lowering of diurnal triglyceride concentrations and a lesser lowering of HDL cholesterol concentrations than in controls (32).…”

Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

“…by guest, on May 12, 2018 www.jlr.org Downloaded from accelerated RCT, is not confi ned to mice but has also been demonstrated to occur in primates and humans ( 18,19 ). Here, we show that the effect of PPAR ␦ on neutral sterol excretion is in part mediated by stimulation of TICE.…”

“…Subsequent cholesterol and apolipoprotein analysis of the lipoprotein profi les in FVB mice revealed a shift from HDL to LDL in both GW610742-treated groups. In contrast, earlier studies in monkeys and humans reported increased HDL cholesterol levels upon PPAR ␦ activation ( 18,19 ). Also in DBA1 mice, PPAR ␦ activation resulted in higher HDL levels ( 20 ).…”

“…PPAR ␦ activation leads to increased levels of HDL cholesterol in primates and humans and enhanced apolipoprotein (Apo)A-I specifi c cholesterol effl ux from THP1 human monocyte cells ( 18,19 ). Van der Veen et al ( 20 ) showed that PPAR ␦ activation resulted in increased fecal neutral sterol output, whereas hepatobiliary cholesterol secretion was unaltered.…”