PPARalpha governs glycerol metabolism.
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 PPARalpha. Furthermore, expression of these genes was induced by the PPARalpha agonist Wy14643 in wild-type but not PPARalpha-null mice. In adipocytes, which express high levels of PPARgamma, expression of cytosolic GPDH was enhanced by PPARgamma and beta/delta agonists, while expression was decreased in PPARgamma(+/-) and PPARbeta/delta(-/-) 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 PPARalpha in hepatic glycerol utilization, administration of synthetic PPARalpha agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPARalpha-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPARalpha on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPARalpha directly governs glycerol metabolism in liver, whereas PPARgamma regulates glycerol metabolism in adipose tissue.
Patsouris
David
D
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
Mandard
Stéphane
S
Voshol
Peter J
PJ
Escher
Pascal
P
Tan
Nguan Soon
NS
Havekes
Louis M
LM
Koenig
Wolfgang
W
März
Winfried
W
Tafuri
Sherrie
S
Wahli
Walter
W
Müller
Michael
M
Kersten
Sander
S
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D017931:DNA Primers; D005786:Gene Expression Regulation; D005990:Glycerol / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D014162:Transfection
D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D005990:Glycerol