Apolipoprotein E gene expression is reduced in apolipoprotein A-I transgenic mice

The levels of plasma apolipoprotein (apo) E, an anti-atherogenic protein in volved in mammalian cholesterol transport, were found to be 2-3 fold lower in mice over-expressing human apoA-I gene. ApoE is mainly associated with V LDL and HDL-size particles, but in mice the majority of the apoE is associa ted with the HDL particles. Over-expression of the human apoA-I in mice inc reases the levels of human apoA-I-rich HDL particles by displacing mouse ap oA-I from HDL. This results in lowering of plasma levels of mouse apoA-I. S ince plasma levels of apoE also decreased in the apoA-I transgenic mice, th e mechanism of apoE lowering was investigated. Although plasma levels of ap oE decreased by 2-3 fold, apoB levels remained unchanged. As expected, the plasma levels of human apoA-I were almost 5-fold higher in the apoAI-Tg mic e compared to mouse apoA-I in WT mice. If the over-expression of human apoA -I caused displacement of apoE from the HDL, the levels of hepatic apoE mRN A should remain the same in WT and the apoAI-Tg mice. However, the measurem ents of apoE mRNA in the liver showed 3-fold decreases of apoE mRNA in apoA I-Tg mice as compared to WT mice, suggesting that the decreased apoE mRNA e xpression, but not the displacement of the apoE from HDL, resulted in the l owering of plasma apoE in apoAI-Tg mice. As expected, the levels of hepatic apoA-I mRNA (transgene) were 5-fold higher in the apoAI-Tg mice. ApoE synt hesis measured in hepatocytes also showed lower synthesis of apoE in the ap oAI-Tg mice. These studies suggest that the integration of human apoA-I tra nsgene in mouse genome occurred at a site that affected apoE gene expressio n. Identification of this locus may provide further understanding of the ap oE gene expression.