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PPARα governs glycerol metabolism
David Patsouris, … , Michael Müller, Sander Kersten
David Patsouris, … , Michael Müller, Sander Kersten
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):94-103. https://doi.org/10.1172/JCI20468.
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Article Metabolism Article has an altmetric score of 4

PPARα governs glycerol metabolism

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Abstract

Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of glycerol, i.e., cytosolic and mitochondrial glycerol 3-phosphate dehydrogenase (GPDH), glycerol kinase, and glycerol transporters aquaporin 3 and 9, are upregulated by fasting in wild-type mice but not in mice lacking PPARα. Furthermore, expression of these genes was induced by the PPARα agonist Wy14643 in wild-type but not PPARα−null mice. In adipocytes, which express high levels of PPARγ, expression of cytosolic GPDH was enhanced by PPARγ and β/δ agonists, while expression was decreased in PPARγ+/– and PPARβ/δ–/– mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments demonstrated that cytosolic GPDH is a direct PPAR target gene. In line with a stimulating role of PPARα in hepatic glycerol utilization, administration of synthetic PPARα agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPARα-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPARα on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPARα directly governs glycerol metabolism in liver, whereas PPARγ regulates glycerol metabolism in adipose tissue.

Authors

David Patsouris, Stéphane Mandard, Peter J. Voshol, Pascal Escher, Nguan Soon Tan, Louis M. Havekes, Wolfgang Koenig, Winfried März, Sherrie Tafuri, Walter Wahli, Michael Müller, Sander Kersten

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Figure 4

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cGPDH is a direct PPARα/γ target gene. Mouse cGPDH reporter constructs c...
cGPDH is a direct PPARα/γ target gene. Mouse cGPDH reporter constructs containing 2240, 560, or 280 bp of immediate upstream promoter region were transfected into NIH-3T3 cells together with a PPARα (A) or PPARγ (B) expression vector. Normalized activity of the full-length cGPDH reporter in the absence of PPAR and ligands was set at 1. (C) Binding of the PPAR/RXR heterodimer to putative response elements, as determined by electrophoretic mobility shift assay. The double-stranded response elements cGPDH-PPRE1 (lanes 1–8). Fold-excess of specific (SC) or nonspecific (NSC) cold probe is indicated. (D) Expression of cGPDH during 3T3-L1 adipogenesis as determined by Q-PCR. Expression at day 8 was set at 100%. ChIP of PPRE within mouse cGPDH promoter using anti-mPPARγ or anti-mPPARα antibodies. Gene sequences spanning the putative PPREs (+1020 to +782) and a random control sequence (+2519 to +2124) were analyzed by PCR in the immunoprecipitated chromatin of 3T3-L1 preadipocytes and adipocytes (E), fed and fasted wild-type and PPARα-null mice (F), and wild-type and PPARα-null mice treated or not with Wy14643 (G). Preimmune serum was used as a control. (H) Transcriptional activity of site-directed mutants (mut) of the cGPDH promoter. Mouse cGPDH reporter constructs containing double nucleotide changes in PPRE1, PPRE2, or both, were transfected into HepG2 cells together with a PPARγ expression vector. Normalized activity of the reporter in the absence of PPAR and ligand was set at 1. Error bars in A, B, and H represent SEM. Cntl, random control sequence; PI, preimmune serum; prom, promoter; Veh, vehicle; Wy, Wy14643; for, forward primer; rev, reverse primer.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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