Expression of peroxisome proliferator-activated receptor alpha, and PPARalpha regulated genes in spontaneously developed hepatocellular carcinomas in fatty acyl-CoA oxidase null mice.
Fatty acyl-CoA oxidase null mice (AOX-/-) develop hepatocellular carcinomas in 100% of animals between 10 and 15 months. We evaluated spontaneously developed HCC in AOX-/- mice for PPARalpha, PPARalpha regulated genes and peroxisome volume density and compared with adjacent non-neoplastic liver and liver in wild-type (AOX+/+) and heterozygous (AOX+/-) mice. The level of PPARalpha mRNA was 2.5-fold higher in HCC compared to the adjacent liver. mRNAs of PPARalpha regulated genes such as peroxisomal bifunctional enzyme, thiolase, cytochrome P450 CYP4A1 and CYP4A3 were similar in HCC and adjacent liver and increased by 7- to 22-fold compared with wild-type and heterozygous mice. Immunoblot analysis of HCC showed high amounts of PPARalpha, peroxisomal bifunctional enzyme and thiolase. Electron microscopic examination revealed 3.8 and 8.3-fold increase in the volume density of peroxisomes in HCC and adjacent liver, respectively, compared to the volume density in wild-type mice. These results demonstrate that spontaneously developed HCC in AOX-/- mice display a similar type of pleiotropic responses to high levels of PPARalpha ligands as the non-neoplastic liver. The changes observed in HCC and adjacent liver in AOX-/- mice were identical to those observed in rats and mice exposed to peroxisome proliferators.
Meyer
Kirstin
K
Department of Pathology, The Feinberg School of Medicine, Chicago, IL 60611-3008, USA.
Jia
Yuzhi
Y
Cao
Wen-Qing
WQ
Kashireddy
Papreddy
P
Rao
M Sambasiva
MS
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004746:Enoyl-CoA Hydratase / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006720:Homozygote; D015151:Immunoblotting; D007535:Isomerases; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000502:physiology*; D063994:Peroxisomal Bifunctional Enzyme; D020675:Peroxisomes / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
C465387:Cyp4a1protein, rat; 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; D002374:Catalase; D000072470:Cytochrome P450 Family 4; C465389:Cyp4a3 protein, rat; D042962:Acyl-CoA Oxidase; D000101:Acetyl-CoA C-Acetyltransferase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases