Thermally Oxidized Oil Increases the Expression of Insulin-Induced Genes and Inhibits Activation of Sterol Regulatory Element-Binding Protein-2 in Rat Liver

Abstract

Administration of oxidized oils to rats or pigs causes a reduction of their cholesterol concentrations in liver and plasma. The reason for this effect is unknown. We tested the hypothesis that oxidized oils lower cholesterol concentrations by inhibiting the proteolytic activation of sterol regulatory element-binding protein (SREBP)-2 in the liver and transcription of its target genes involved in cholesterol synthesis and uptake through an upregulation of gene expression of insulin-induced genes (Insig). For 6 d, 18 rats were orally administered either sunflower oil (control group) or an oxidized oil prepared by heating sunflower oil. Rats administered the oxidized oil had higher messenger RNA (mRNA) concentrations of acyl-CoA oxidase and cytochrome P450 4A1 in the liver than control rats (P < 0.05), indicative of activation of PPARα. Furthermore, rats administered the oxidized oil had higher mRNA concentrations of Insig-1 and Insig-2a, a lower concentration of the mature SREBP-2 in the nucleus, lower mRNA concentrations of the SREBP-2 target genes 3-hydroxy-3-methylglutaryl CoA reductase and LDL receptor in their livers, and a lower concentration of cholesterol in liver, plasma, VLDL, and HDL than control rats (P < 0.05). In conclusion, this study shows that reduced cholesterol concentrations in liver and plasma of rats administered an oxidized oil were due to an inhibition of the activation of SREBP-2 by an upregulation of Insig, which in turn inhibited transcription of proteins involved in hepatic cholesterol synthesis and uptake.