A critical role for the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the cellular fasting response: The PPAR alpha-null mouse as a model of fatty acid oxidation disorders

We hypothesized that the lipid-activated transcription factor, the peroxiso me proliferator-activated receptor cu (PPAR alpha), plays a pivotal role in the cellular metabolic response to fasting, Short-term starvation caused h epatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR alpha (PPAR alpha( -/-)), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR alph a(+/+) mice, fasting induced the hepatic and cardiac expression of PPAR alp ha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydroge nase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA ox idase, cytochrome p450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR alpha target genes was not induced by fasti ng in PPAR alpha(-/-) mice, These results define a critical role for PPAR a lpha in a transcriptional regulatory response to fasting and identify the P PAR alpha(-/-) mouse as a potentially useful murine model of inborn and acq uired abnormalities of human fatty acid utilization.