Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta.
Peroxisome proliferator activated receptors (PPARs) are nuclear receptors activated by small, lipophilic compounds. Typically resident on nuclear DNA, full activation requires heterodimer formation with retinoid X receptor and ligand binding, leading to modulation in the expression of hundreds of genes. Of the 3 described forms, (PPAR-alpha, PPAR-gamma, and PPAR-delta), PPAR-delta has been the least investigated. Preclinical in vitro data show that activation of PPAR-delta, like PPAR-alpha, results in enhancement of fatty acid oxidation, leading to increased energy production in the form of adenosine triphosphate and of energy uncoupling. Microarray data in preclinical models suggest substantial PPAR-delta expression in skeletal muscle. Exercise, which induces upregulation of PPAR-delta in muscle tissue, leads to an increased requirement for an external or serum derived triacylglycerol energy source. This suggests that upregulation of skeletal muscle PPAR-delta would influence lipoprotein composition, this being the major source of combustible substrate. In the first human study using a PPAR-delta agonist, experimental data obtained with GW 501516 (a highly specific PPAR-delta agonist) suggested that upregulated enzymes critical to fatty acid oxidation in human cells enhanced fatty acid and beta-oxidation in skeletal muscle.
Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. Dennis.L.Sprecher@gsk.com
Dennis L
DL
Sprecher
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D015854:Up-Regulation
D005227:Fatty Acids; C425931:GW 501516; D008074:Lipoproteins; D047494:PPAR delta; D013844:Thiazoles; D000255:Adenosine Triphosphate