Peroxisome proliferator-activated receptor gamma and c/ebpalpha synergistically activate key metabolic adipocyte genes by assisted loading

Peroxisome proliferator-activated receptor (PPAR) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction between Wy14643 and fasting. Numerous genes were commonly regulated in liver between the two treatments, including many classical PPAR target genes, such as Aldh3a2 and Cpt2. Remarkably, several genes induced by Wy14643 were upregulated by fasting independently of PPAR, including Lpin2 and St3gal5, suggesting involvement of another transcription factor. Using chromatin immunoprecipitation, Lpin2 and St3gal5 were shown to be direct targets of PPAR/ during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPAR. Binding of PPAR/ to the Lpin2 and St3gal5 genes followed the plasma free fatty acid (FFA) concentration, consistent with activation of PPAR/ by plasma FFAs. Subsequent experiments using transgenic and knockout mice for Angptl4, a potent stimulant of adipose tissue lipolysis, confirmed the stimulatory effect of plasma FFAs on Lpin2 and St3gal5 expression levels via PPAR/. In contrast, the data did not support activation of PPAR by plasma FFAs. The result