| The peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that transcriptionally regulates mitochondrial, microsomal and peroxisomal fatty acid oxidation enzymes in the liver. Ligands for PPARα include synthetic peroxisome proliferators and some fatty acids and fatty acid metabolites. Sustained PPARα activation leads to predictable pleiotropic responses in liver including peroxisome proliferation, increased fatty acid oxidation, and hepatocellular carcinoma.;During fasting, fatty acids that are stored in adipose tissue are mobilized through the blood to the liver to be metabolized. The liver must increase the rate of fat metabolism to respond to increased demand. PPARα −/− mice, unlike wild type, are unable to respond to elevated fatty acid levels in the liver resulting in a dramatic accumulation of fat in the liver of these animals. The ribonuclease protection assay was used to show that no increase in PPARα mRNA was required for the fasting response in the wild type mice, and that no other PPAR family member was transcriptionally activated in response to fasting.;The developmental activation of PPARα in mice nullizygous for fatty acyl-CoA oxidase (AOX−/−), the first enzyme in the peroxisomal VLCFA β-oxidation pathway, was also investigated, PPARα-responsive mRNA levels were analyzed in wild type and AOX−/− embryos and neonatal siblings using in situ hybridization. Elevated mRNA levels indicating PPARα activation were detected in newborn AOX−/− mouse livers, but not in embryonic livers, indicating that VLCFAs do not accumulate in the livers of AOX−/− mice until after birth. PPARα is activated in AOX−/− mice from birth throughout life.;PPARα activation was also analyzed in the heart and kidney, two extrahepatic organs that also rely upon fat metabolism. Total RNA and proteins were extracted from the heart, kidney, and liver of ciprofibrate-treated and control mice. PPARα-responsive mRNAs and proteins were analyzed by ribonuclease protection and Western analysis, respectively. PPARα-responsive genes were strongly induced in the liver, weakly induced in the kidney, and no induction was observed in the heart. PPARα mRNA was detected in all tissues, suggesting that other factors such as co-factors are important in regulating the specificity of PPARα function. |
