Nutrigenomics Consortium, TI Food and Nutrition, Nieuwe Kanaal 9A, 6709 PA Wageningen, the Netherlands; Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, the Netherlands; Department of Biochemistry, University of Kuopio, 70211 Kuopio, Finland; Departments of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands; Centre Intégrative Génomique, University of Lausanne, Switzerland.

PPARalpha is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically 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 PPARalpha target genes such as Aldh3a2 and Cpt2. Remarkably, several genes induced by Wy14643 were upregulated by fasting independently of PPARalpha, including Lpin2 and St3gal5, suggesting involvement of another transcription factor. Using chromatin immunoprecipitation, Lpin2 and St3gal5 were shown to be direct targets of PPARbeta/delta during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPARalpha. Binding of PPARbeta/delta to the Lpin2 and St3gal5 genes followed the plasma FFA concentration, consistent with activation of PPARbeta/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 via PPARbeta/delta. In contrast, the data did not support activation of PPARalpha by plasma FFA. The results identify Lpin2 and St3gal5 as novel PPARbeta/delta target genes and show that upregulation of gene expression by PPARbeta/delta is sensitive to plasma FFA levels. In contrast, this is not the case for PPARalpha, revealing a novel mechanism for functional differentiation between PPARs.

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