Peroxisome Proliferator-Activated Receptor β/δ (PPARβ/δ) but Not PPARα Serves as a Plasma Free Fatty Acid Sensor in Liver

Peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 alpha target genes, such as Aldh3a2 and Cpt2. Remarkably, several genes induced by Wy14643 were upregulated by fasting independently of PPAR alpha, including Lpin2 and St3gal5, suggesting involvement of another transcription factor. Using chromatin immunoprecipitation, Lpin2 and St3gal5 were shown to be direct targets of PPAR beta/delta during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPAR alpha. Binding of PPAR beta/delta to the Lpin2 and St3gal5 genes followed the plasma free fatty acid (FFA) concentration, consistent with activation of PPAR beta/delta 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 beta/delta. In contrast, the data did not support activation of PPAR alpha by plasma FFAs. The results identify Lpin2 and St3gal5 as novel PPAR beta/delta target genes and show that upregulation of gene expression by PPAR beta/delta is sensitive to plasma FFA levels. In contrast, this is not the case for PPAR alpha, revealing a novel mechanism for functional differentiation between PPARs.