Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting

Citation
S. Kersten et al., Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting, J CLIN INV, 103(11), 1999, pp. 1489-1498
Citations number
51
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
0021-9738 → ACNP
Volume
103
Issue
11
Year of publication
1999
Pages
1489 - 1498
Database
ISI
SICI code
0021-9738(199906)103:11<1489:PPRAMT>2.0.ZU;2-3
Abstract
Prolonged deprivation of food induces dramatic changes in mammalian metabol ism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor kno wn as peroxisome proliferator-activated receptor alpha (PPAR alpha) was fou nd to play a role in regulating mitochondrial and peroxisomal fatty acid ox idation, suggesting that PPAR alpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPAR alpha-null mice were subjected to a high fat diet or to fasting, and their responses were c ompared with those of wild-type mice. PPAR alpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A s imilar phenotype was noted in PPAR alpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevat ed plasma free Fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased r equirement for hepatic fatty acid oxidation, PPAR alpha mRNA is induced dur ing fasting in wildtype mice. The data indicate that PPARa plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPAR alpha stimulates hepatic fatty acid oxidation to supply su bstrates that can be metabolized by other tissues.