Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. The three isoforms (PPARalpha, beta/delta and gamma) have been implicated in the regulation of the expression of genes involved in lipid metabolism. Although their prominent role in lipid homeostasis is well established, the way in which the activity of each of the PPAR isoforms is regulated under physiological and pathological conditions is still subject of intensive research. In skeletal as well as cardiac muscle cells it has been demonstrated that the expression of a large panel of proteins involved in the transport and metabolic conversion of fatty acids is under control of PPARs. The pivotal role of the PPARalpha isoform in cardiac fatty acid metabolism has been confirmed in PPARalpha-null mice. The exact role of PPARbeta/delta in the regulation of muscle metabolism is still a matter of debate. Whereas several studies provided evidence to support the notion that PPARalpha and PPARbeta/delta have redundant roles, other studies suggest that PPARalpha activity is counteracted by PPARbeta/delta. Marked effects of bona fide PPARgamma ligands (the antidiabetic thiazolidinediones) on skeletal and cardiac muscle function and phenotype, have also been reported. However, next to activating PPARgamma, the thiazolidinediones do affect other cellular processes as well. To date it is being realized that the control of the trans-activating capacity of each of the PPAR isoforms is multi-factorial and, in addition to ligand availability, depends on such factors as isoform-specific phosphorylation and selective interaction with various proteins acting either as co-activator or co-repressor.