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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

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 1

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Oligonucleotide microarray analysis identifies novel putative PPARα targ...
Oligonucleotide microarray analysis identifies novel putative PPARα target genes. (A) Relative expression of PPARα in liver was determined by Q-PCR in fed and 24-hour-fasted mice (n = 4). The difference was evaluated by Student’s t test (P < 0.01). Error bars represent SEM. (B) Expression of genes involved in fatty acid oxidation and ketogenesis in livers of wild-type and PPARα-null mice, as determined by oligonucleotide microarray (Affymetrix). The average difference (expression) of wild-type at 0 hours was arbitrarily set at 100. Filled diamonds: long-chain fatty acyl-CoA synthetase; open diamonds: carnitine palmitoyltransferase II; filled triangles: long-chain acyl-CoA dehydrogenase; open circles: short-chain acyl-CoA dehydrogenase; open triangles: medium-chain acyl-CoA dehydrogenase; filled circles: dodecenoyl-CoA δ-isomerase; filled squares: HMG-CoA synthase; open squares: HMG-CoA lyase. (C) Hepatic expression of PEPCK (left), cGPDH (middle) and mGPDH (right) after 0, 2.5, 5.5 and 24 hours fasting in wild-type and PPARα-null mice according to oligonucleotide microarray. The average difference (expression) of wild-type at 0 hours was arbitrarily set at 100.

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

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