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

Abstract

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 anti-diabetic 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.

New strategies in sport nutrition to increase exercise performance

“…The AMPK dependent phosphorylation of PGC-1α additionally is associated with an increase in the expression of mitochondrial genes [28]. As we mentioned PGC-1α acts as a transcriptional co-activator where it moderates the activity of multiple transcription factors including the PPAR's (PPAR-γ, PPAR-α and PPAR-δ), mitochondrial transcription factor A (TFAM), nuclear respiratory factors 1/2 (NRF1/2) and estrogen related receptor-α (ERR-α) (Figure 1) [32]. The PPAR's are also of interest with regard to nutritional interventions as they are sensitive to changes in fatty acid levels in that increased free fatty acid (FFA) availability leads to increases in the activity of these transcription factors which control the expression of FFA metabolism genes [33].…”

Identification and validation of an ERBB2 gene expression signature in breast cancers

“…Tiwari et al (1991) reported a relationship between ERBB2, fatty acids and 2 0 ,5 0 oligoadenylate synthetases (OAS2), which is included in our 'ERBB2 cluster'. Peroxisome proliferator-activated receptors (PPARs) are known regulators of lipid metabolism; their trans-activating capacity depends on the recruitment of auxiliary proteins (for a review, see Gilde and van Bilsen, 2003); modifications of fatty acid metabolism in ERBB2 þ tumours may thus be simply associated with overexpression of PPARBP.…”

Adipose Tissue and Skeletal Muscle Plasticity in Obesity and Metabolic Disease

“…It cooperates with transcription factor PGC1, overexpression of which has been demonstrated to enhance both lipid oxidation and synthesis (Espinoza et al 2010). Another possibility is that palmitate is a ligand for the transcription factors involved in the regulation of cell´s oxidative capacity, such as PPAR (Gilde & Van Bilsen 2003). Animal (Hancock et al 2008) as well as clinical studies (Bajaj et al 2007) also support the role of fatty acids for PGC1 regulation at the level of gene expression.…”

“…Fatty acids are known to be the ligands of various transcription factors involved in the regulation of metabolism and mitochondrial biogenesis (Gilde & Van Bilsen 2003). It has been shown previously that fatty acids as well as a diet with an increased fat content is capable of inducing mitochondrial biogenesis both in vitro and in vivo (Watt et al 2006;Hancock et al 2008).…”