Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice.
Mice deficient in fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal beta-oxidation system, develop specific morphological and molecular changes in the liver characterized by microvesicular fatty change, increased mitosis, spontaneous peroxisome proliferation, increased mRNA and protein levels of genes regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), and hepatocellular carcinoma. Based on these findings it is proposed that substrates for AOX function as ligands for PPARalpha. In this study we examined the sequential changes in morphology and gene 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(-/-) mice high levels of expression of PPARalpha-responsive genes in the liver commenced on the day of birth and persisted throughout the postnatal period. We found no indication of PPARalpha 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 extensive steatosis and the presence in the periportal areas of clusters of hepatocytes with abundant granular eosinophilic cytoplasm rich in peroxisomes. These results suggest that the biological ligands for PPARalpha vis a vis substrates for AOX either are not functional in fetal liver or do not cross the placental barrier during the fetal development and that postnatally they are likely derived from milk and diet.
Cook
W S
WS
Department of Pathology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
Jain
S
S
Jia
Y
Y
Cao
W Q
WQ
Yeldandi
A V
AV
Reddy
J K
JK
Rao
M S
MS
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015151:Immunoblotting; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007535:Isomerases; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D063994:Peroxisomal Bifunctional Enzyme; D020675:Peroxisomes / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D007527:Isoenzymes; D008024:Ligands; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D042962:Acyl-CoA Oxidase; D000102:Acetyl-CoA C-Acyltransferase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases