A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders.
We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), 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 PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha 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 PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.
Leone
T C
TC
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Weinheimer
C J
CJ
Kelly
D P
DP
D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D044944:Acyl-CoA Dehydrogenases; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase