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Analysis of the structure and function relationship of human apolipoprotein E in vivo, using adenovirus‐mediated gene transfer
Author(s) -
Kypreos Kyriakos E.,
Teusink Bas,
Dijk K. O. Willems,
Havekes Louis M.,
Zannis Vassilis I.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0882fje
Subject(s) - gene transfer , in vivo , apolipoprotein e , structure function , function (biology) , plant lipid transfer proteins , gene , apolipoprotein b , computational biology , biology , microbiology and biotechnology , virology , genetics , medicine , biochemistry , disease , physics , cholesterol , particle physics
We have used adenovirus‐mediated gene transfer in apolipoprotein E (apoE)‐deficient mice (E −/− ) to dissect the domains of apoE required for cholesterol and triglyceride homeostasis in vivo. A dose of 2 × 10 9 pfu of apoE2‐ apoE3‐, or apoE4‐expressing adenoviruses failed to decrease the cholesterol levels of E −/− mice and caused severe hypertriglyceridemia, characterized by accumulation of apoE‐rich and triglyceride‐rich very low density lipoprotein (VLDL). In contrast, the truncated forms apoE4–229 and apoE4–259 at doses of 2 × 10 9 pfu, or 4 × 10 9 pfu, resulted in a 90% reduction in the cholesterol levels of E −/− mice, without affecting plasma triglyceride levels. The triglyceride secretion of mice infected with apoE4 was increased 2.7‐fold compared with that of mice infected with apoE4–259. The apoE truncations did not influence apoE secretion by cells and association with VLDL. The levels of apoE4 and apoE4–229 and apoE4–259 mRNA in the livers of infected animals were similar. The findings suggest that the amino‐terminal 1–229 region of apoE4 contains the domains required for the association of apoE with lipoproteins and their subsequent clearance via apoE‐recognizing receptors. Furthermore, the carboxy‐terminal 260–299 residues of apoE contribute to the apoE‐induced hypertriglyceridemia. Thus, truncated forms of apoE may find useful future application in gene therapy for correction of high cholesterol profiles without triggering hypertriglyceridemia.