Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidasenull mice

Mice deficient in fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of th e peroxisomal beta -oxidation system, develop specific morphological and mo lecular changes in the liver characterized by microvesicular fatty change, increased mitosis, spontaneous peroxisome proliferation, increased m-RNA an d protein levels of genes regulated by peroxisome proliferator-activated re ceptor alpha (PPAR alpha), and hepatocellular carcinoma. Based on these fin dings it is proposed that substrates for AOX function as ligands for PPAR a lpha. In this study we examined the sequential changes in morphology and ge ne expression in the liver of wild-type and AOX(-/-) mice at Embryonic Day 17.5, and during postnatal development up to 2 months of age. In AOX(-/-) m ice high levels of expression of PPAR alpha -responsive genes in the liver commenced on the day of birth and persisted throughout the postnatal period . We found no indication of PPAR alpha activation in the livers of AOX(-/-) mice at embryonic age E17.5. In AOX(-/-) mice microvesicular fatty change in liver cells was evident at 7 days. At 2 months of age livers showed exte nsive steatosis and the presence in the periportal areas of clusters of hep atocytes with abundant granular eosinophilic cytoplasm rich in peroxisomes. These results suggest that the biological ligands for PPAR alpha vis a vis substrates for AOX either are not functional in fetal liver or do not cros s the placental barrier during the fetal development and that postnatally t hey are likely derived from milk and diet. (C) 2001 Academic Press.