The regulation of apolipoprotein A-I gene expression: Dietary copper and zinc

Abstract

Copper (Cu) deficiency was induced in rats and Hep G2 cells by the use of a Cu-deficient diet and a cupruretic chelator, respectively. In the rat liver, Cu-deficiency did not alter the apo A-I mRNA abundance, but shifted significant amounts of mRNA to translationally more active fractions. These findings indicated that an increase in translational efficiency may contribute to the increase in hepatic apo A-I synthesis observed in Cu-deficient rats. In Hep G2 cells, Cu-depletion elevated the cytoplasmic apo A-I mRNA abundance by 1.5-fold. A 2.5-fold increased transcription rate and a 2-fold accelerated mRNA decay were also established in Cu-depleted cells. These changes appeared to be specific to Cu depletion, because they were reversed by Cu repletion. Moreover, the cytoplasmic mRNA abundance of HNF-4, a major transcription activator of apo A-I gene, was elevated by 1.6-fold in Cu-depleted cells. Thus the elevated cellular apo A-I mRNA level may have resulted from an accelerated mRNA turnover, and subsequently contributed to the enhanced apo A-I synthesis and secretion observed in Cu-depleted cells. Zinc (Zn) deficiency was induced in animals and Hep G2 cells by the use of Zn-deficient diet and medium, respectively. Plasma HDL apo A-I levels was reduced 18% in hamsters and 13% in rats. Whereas Zn repletion normalized plasma apo A-I to the control level in hamsters and increased it by 34% in rats. No treatment difference was detected in the intestinal apo A-I mRNA abundance in both species, although the hepatic abundance was reduced by 18% and 55% in Zn-deficient hamsters and rats, respectively. Subsequent Zn-repletion normalized the mRNA abundance to the control level in hamsters and elevated it by 41% in rats. As compared to control Hep G2 cells, the cellular Zn content and apo A-I mRNA abundance were reduced by 55% and 20% in Zn-depleted cells, but increased by 64% and 11% in Zn-supplemented cells, respectively. Furthermore, Zn-repletion completely normalized the effects of Zn-depletion. Thus the depletion of hepatic Zn content may cause the reductions in hepatic apo A-I mRNA abundance and plasma apo A-I pool observed in Zn deficiency.