Markedly increased secretion of VLDL triglycerides induced by gene transfer of apolipoprotein E isoforms in apoE-deficient mice

Apolipoprotein E (apoE) plays a key role in the receptor-mediated uptake of lipoproteins by the liver and therefore in regulating plasma levels of lip oproteins. ApoE may also facilitate hepatic secretion of very low density l ipoprotein (VLDL) triglyceride (TG), We directly tested the hypothesis that reconstitution of hepatic apoE expression in adult apoE-deficient mice by gene transfer would acutely enhance VLDL-TG production and directly compare d the three major human apoE isoforms using this approach. Second generatio n recombinant adenoviruses encoding the three major isoforms of human apoE (E2, E3, and E4) or a control virus were injected intravenously into apoE-d eficient mice, resulting in acute expression of the apoE isoforms in the li ver. Despite the expected decreases in total and VLDL cholesterol levels, a poE expression was associated with increased total and VLDL triglyceride le vels (E2 > E4 > E3), The increase in TG levels significantly correlated wit h plasma apoE concentrations. In order to determine whether acute apoE expr ession influenced the rate of VLDL-TG production, additional experiments we re performed. Three days after injection of adenoviruses, Triton WR1339 was injected to block lipolysis of TG-rich lipoproteins and VLDL- TG productio n rates were determined. Mice injected with control adenovirus had a mean V LDL-TG production rate of 74 +/- 7 mu mol/h/kg. In contrast, VLDL-TG produc tion rates in apoE-expressing mice were 363 +/- 162 mu mol/h/kg, 286 +/- 17 5 mu mol/h/kg, and 300 +/- 84 mu mol/h/kg for apoE2, apoE3, and apoE4, resp ectively, The VLDL-TG production rates in apoE-expressing mice were all sig nificantly greater than in control mice but were not significantly differen t from each other. jlr In summary, acute expression of all three human apoE isoforms in livers of apoE-deficient mice markedly increased VLDL-TG produ ction to a similar degree, consistent with the concept that apoE plays an i mportant role in facilitating hepatic VLDL-TG production in an isoform-inde pendent manner.