Sander Kersten
PRI, Wageningen
Fasting is associated with pronounced changes in hepatic energy metabolism. These adaptive changes are partially driven by alterations in the expression of enzymes and transcription factors. To gain more insight into the effects of fasting on hepatic gene expression, oligonucleotide micro-array (Affymetrix) was used. It was found that fasting results in pronounced changes in hepatic gene expression (about one-third of the total number of genes), in a time-dependent manner. The expression of numerous genes implicated in lipogenesis, glycogen synthesis/glycolysis, cholesterol/bile acid synthesis, and amino acid & nucleotide metabolism was decreased by fasting, while genes involved in fatty acid oxidation and gluconeogenesis were stimulated. Using mice that lack the peroxisome proliferator activated receptor alpha (PPARa), it is shown by micro-array that this transcription factor plays an important role in the transcriptional regulation of hepatic energy homeostasis during fasting. Deletion of PPARa resulted in decreased expression of genes involved in fatty acid oxidation and gluconeogenesis, and increased expression of genes involved in biotransformation, the cytochrome p450 system, and amino acid metabolism. These changes in gene expression lead to a severe fasting-induced phenotype characterized by hypoglycemia, hypoketonemia, elevated plasma free fatty acid and urea levels, hypothermia, and a fatty liver. These results demonstrate that PPARa has a pivotal role in the adaptive response to fasting.