The transactivation potential of PPARα can be stimulated either by PPARα ligands or by the presence of high levels of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), as occurs during fasting [6]. Moreover, the induction/suppression of PPARα target genes will also depend on PPARα expression levels which are in part autoregulated [6]. Since nonesterified fatty acids are known ligands for PPARα, elevated plasma free fatty acids (FFAs) could be expected to act as endogenous PPARα ligands during fasting and to mediate the fasting-induced metabolic effects. Surprisingly, it was shown that this activation of hepatic PPARα does not occur by plasma FFAs [6, 7], but by fatty acids synthesized in hepatocytes de novo [7, 8]. Hepatic PPARβ/δ rather than PPARα was shown to be responsive to elevated fasting plasma FFAs levels [6]. Moreover, also dietary fatty acids have been reported to be able to activate PPARα [9–11].
