Role of hypolipidemic drug clofibrate in altering iron regulatory proteins IRP1 and IRP2 activities and hepatic iron metabolism in rats fed a low-iron diet

Abstract

In addition to reducing the expression of transferrin and ceruloplasmin genes, hypolipidemic peroxisome proliferators may alter iron homeostasis in the liver. Therefore, this study investigates the effects of clofibrate on proteins related to liver iron metabolism in a rat model using a 2 x 2 experimental design: two dose levels of clofibrate in diet (0 and 0.5%) and two dietary iron levels (35 ppm as normal level and 15 ppm as low-iron diet). Twenty-four Wistar rats were assigned to the four diets and fed for 6 weeks. Subsequent measurements of iron parameters in the blood and the liver indicated that, in addition to mild anemia and the reduction in serum iron and total iron-binding capacity, clofibrate treatment altered IRP1 and IRP2 activities differentially and increased mitochondrial aconitase both at activity and protein levels. At both normal and low-iron intakes, clofibrate caused a 50% reduction in serum iron and TIBC with a corresponding reduction in transferrin mRNA. The RNA-binding activities of IRP1 were selectively activated by clofibrate treatment even though liver iron concentration was not depleted. The RNA-binding activity of IRP2 was selectively activated by the low iron intake and correlated with an increase of transferrin receptor mRNA, while clofibrate treatment offset the effects of the low iron intake.