Pretranslational upregulation of microsomal CYP4A in rat liver by intake of a high-sucrose, lipid-devoid diet containing orotic acid

Abstract

In rodents, high-fat diets promote hepatic lipid accumulation in rodents, activation of peroxisome proliferator activated receptor-α (PPARα) 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 PPARα activation in rodent liver. CYP4A protein and laurate ω-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 PPARα protein was decreased by the S/OA-diet but was increased to 5.7-fold of control by clofibric acid; retinoid X-receptor-α (RXRα) protein was decreased to 26–41% of control by all treatments. In further studies, administration of the S/OA-diet to control and PPARα-null mice promoted hepatic lipid deposition; microsomal CYP4A protein was induced in wild-type but not PPARα-null mice. These findings implicate PPARα in the induction of CYP4A in rodent liver by the lipid-devoid S/OA-diet. Decreased availability of hepatic PPARα and RXRα after intake of the diet may contribute to the selective upregulation of hepatic CYP4A1 and CYP4A2 in this model.