title: Peroxisome proliferator-activated receptor-delta, a regulator of oxidative capacity, fuel switching and cholesterol transport.
abstract: Synthetic agonists of peroxisome proliferator-activated receptor (PPAR)-delta have shown a promising pharmacological profile in preclinical models of metabolic and cardiovascular disease. At present, the pharmaceutical development of these drugs exploits the potential to raise plasma HDL-cholesterol in animals and their insulin-sensitising and glucose-lowering properties. PPAR-delta agonists have also proven to be powerful research tools that have provided insights into the role of fatty acid metabolism in human physiology and disease. Activation of PPAR-delta induces the expression of genes important for cellular fatty acid combustion and an associated increase in whole-body lipid dissipation. The predominant target tissue in this regard is skeletal muscle, in which PPAR-delta activation regulates the oxidative capacity of the mitochondrial apparatus, switches fuel preference from glucose to fatty acids, and reduces triacylglycerol storage. These changes counter the characteristic derangements of insulin- resistant skeletal muscle but resemble the metabolic adaptation to regular physical exercise. Apart from effects on fuel turnover, there is evidence for direct antiatherogenic properties, because PPAR-delta activation increases cholesterol export and represses inflammatory gene expression in macrophages and atherosclerotic lesions. Whereas conclusions about the full potential of PPAR-delta as a drug target await the result of large scale clinical testing, ongoing investigation of this nuclear receptor has greatly improved our knowledge of the physiological regulation of whole-body fuel turnover and the interdependence of mitochondrial function and insulin sensitivity.
authors.affiliation: Department of Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria. clemens.fuernsinn@meduniwien.ac.at.
authors.forename: C
authors.initials: C
authors.lastname: Fürnsinn
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
authors.forename: B
authors.initials: B
authors.lastname: Brunmair
mesh_terms: D050197:Atherosclerosis / Q000503:physiopathology; D008076:Cholesterol, HDL / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D047494:PPAR delta / Q000502:physiology*
chemical_list: D008076:Cholesterol, HDL; D047494:PPAR delta; D005947:Glucose