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Molecular and Cellular Biology, December 2009, p. 6257-6267, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00370-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Peroxisome Proliferator-Activated Receptor β/{delta} (PPARβ/{delta}) but Not PPAR{alpha} Serves as a Plasma Free Fatty Acid Sensor in Liver {triangledown} ,{dagger}

Linda M. Sanderson,1,2 Tatjana Degenhardt,3 Arjen Koppen,4,5 Eric Kalkhoven,4,5 Beatrice Desvergne,6 Michael Müller,1,2 and Sander Kersten1,2*

Nutrigenomics Consortium, TI Food and Nutrition, Nieuwe Kanaal 9A, 6709 PA Wageningen, The Netherlands,1 Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands,2 Department of Biochemistry, University of Kuopio, 70211 Kuopio, Finland,3 Departments of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands,4 Netherlands Metabolomics Center, Leiden, The Netherlands,5 Centre Intégrative Génomique, University of Lausanne, Lausanne, Switzerland6

Received 23 March 2009/ Returned for modification 26 April 2009/ Accepted 14 September 2009

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 PPARβ/{delta} during fasting, whereas Aldh3a2 and Cpt2 were exclusive targets of PPAR{alpha}. Binding of PPARβ/{delta} to the Lpin2 and St3gal5 genes followed the plasma free fatty acid (FFA) concentration, consistent with activation of PPARβ/{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 PPARβ/{delta}. In contrast, the data did not support activation of PPAR{alpha} by plasma FFAs. The results identify Lpin2 and St3gal5 as novel PPARβ/{delta} target genes and show that upregulation of gene expression by PPARβ/{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.

* Corresponding author. Mailing address: Nutrition, Metabolism and Genomics Group, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands. Phone: 31 317 485787. Fax: 31 317 483342. E-mail: sander.kersten{at}wur.nl

{triangledown} Published ahead of print on 5 October 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2009, p. 6257-6267, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00370-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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