A Critical Role for the Peroxisome Proliferator-Activated Receptor α (PPARα) in the Cellular Fasting Response: The PPARα -Null Mouse as a Model of Fatty Acid Oxidation Disorders
Abstract
We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor α (PPARα), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARα (PPARα-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARα+/+ mice, fasting induced the hepatic and cardiac expression of PPARα target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARα target genes was not induced by fasting in PPARα-/- mice. These results define a critical role for PPARα in a transcriptional regulatory response to fasting and identify the PPARα-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- June 1999
- DOI:
- 10.1073/pnas.96.13.7473
- Bibcode:
- 1999PNAS...96.7473L