Pretranslational upregulation of microsomal CYP4A in rat liver by intake of a high-sucrose, lipid-devoid diet containing orotic acid.
In rodents, high-fat diets promote hepatic lipid accumulation in rodents, activation of peroxisome proliferator activated receptor-alpha (PPARalpha) and upregulation of cytochrome P450 (CYP) 4A gene expression. Lipid-devoid diets containing sucrose and orotic acid (S/OA-diet) also cause lipid infiltration by stimulating intrahepatic lipid synthesis and preventing lipoprotein transport through the Golgi apparatus. This study evaluated the impact of the lipid-deficient S/OA-diet on CYP4A expression and PPARalpha activation in rodent liver. CYP4A protein and laurate omega-hydroxylation activity were increased in rat liver after S/OA-feeding for 21 days. CYP4A1 and CYP4A2 mRNAs were induced to 2.1- and 2.6-fold of control, but mRNAs corresponding to CYP4A3 and the peroxisomal acyl-CoA oxidase (AOX) were unchanged. Coadministration of clofibric acid and the S/OA-diet prevented hepatic lipid accumulation and upregulated CYP4A protein to levels comparable with clofibric acid alone (five-fold of control). Clofibric acid, alone and in combination with the S/OA-diet, upregulated CYP4A1-3 and AOX mRNAs. Hepatic PPARalpha protein was decreased by the S/OA-diet but was increased to 5.7-fold of control by clofibric acid; retinoid X-receptor-alpha (RXRalpha) protein was decreased to 26-41% of control by all treatments. In further studies, administration of the S/OA-diet to control and PPARalpha-null mice promoted hepatic lipid deposition; microsomal CYP4A protein was induced in wild-type but not PPARalpha-null mice. These findings implicate PPARalpha in the induction of CYP4A in rodent liver by the lipid-devoid S/OA-diet. Decreased availability of hepatic PPARalpha and RXRalpha after intake of the diet may contribute to the selective upregulation of hepatic CYP4A1 and CYP4A2 in this model.
Su
Gloria M
GM
Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.
Fiala-Beer
Eva
E
Weber
Jan
J
Jahn
Dennis
D
Robertson
Graham R
GR
Murray
Michael
M
D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology*; D009963:Orotic Acid / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013395:Sucrose / Q000008:administration & dosage*; D015854:Up-Regulation
D013395:Sucrose; D009963:Orotic Acid; D042926:Cytochrome P-450 CYP4A