The aminoterminal 1-185 domain of human apolipoprotein E suffices for the de novo biogenesis of apoE-containing HDL-like particles in apoA-I deficient mice.

AIMS

Recently we showed that apolipoprotein E promotes the de novo biogenesis of apoE-containing HDL particles in a process that requires the function of the lipid transporter ABCA1. Here, we sought to identify the domain of apoE that is responsible for its functional interactions with ABCA1 and the formation of apoE-rich HDL-like particles.

METHODS AND RESULTS

Recombinant attenuated adenoviruses expressing carboxy-terminal truncated forms of apoE4 (apoE4[1-259], apoE4[1-229], apoE4[1-202], and apoE4[1-185]) were administered to apoA-I-deficient mice at a low dose of 8×10(8) pfu and five days post-infection plasma samples were isolated and analyzed for HDL formation. Fractionation of plasma lipoproteins of the infected mice by density gradient ultracentrifugation and FPLC revealed that all forms were capable of promoting HDL formation. Negative staining electron microscopy analysis of the HDL density fractions confirmed that all C-terminal truncated forms of apoE4 promoted the formation of particles with diameters in the HDL region. Interestingly, apoE4[1-259], apoE4[1-229], and apoE4[1-202] led to the formation of spherical particles while plasma from apoE4[1-185] expressing mice contained a mixture of spherical and discoidal particles.

CONCLUSIONS

Taken together, our data establish that the aminoterminal 1-185 region of apoE suffices for the formation of HDL particles in vivo. Our findings may have important ramifications in the design of new biological drugs for the treatment of dyslipidemia, atherosclerosis and coronary heart disease.