Domains of Apolipoprotein E Contributing to Triglyceride and Cholesterol Homeostasis in Vivo

• Published in: The Journal of biological chemistry Vol. 276; no. 23; pp. 19778 - 19786
• Main Authors: Kypreos, Kyriakos E., van Dijk, Ko Willems, van der Zee, Andre, Havekes, Louis M., Zannis, Vassilis I.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.01.2001; American Society for Biochemistry and Molecular Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M100418200

Apolipoprotein (apo) E has been implicated in cholesterol and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficient clearance of apoE-containing lipoprotein remnants. However, high apoE plasma levels correlate with high plasma triglyceride levels. We have used adenovirus-mediated gene transfer in apoE-deficient mice (E−/−) to define the domains of apoE required for cholesterol and triglyceride homeostasis in vivo. A dose of 2 × 109 plaque-forming units of apoE4-expressing adenovirus reduced slightly the cholesterol levels of E−/− mice and resulted in severe hypertriglyceridemia, due to accumulation of cholesterol and triglyceride-rich very low density lipoprotein particles in plasma. In contrast, the truncated form apoE4–202 resulted in a 90% reduction in the plasma cholesterol levels but did not alter plasma triglyceride levels in the E−/− mice. ApoE secretion by cell cultures, as well as the steady-state hepatic mRNA levels in individual mice expressing apoE4 or apoE4–202, were similar. In contrast, very low density lipoprotein-triglyceride secretion in mice expressing apoE4, but not apoE4–202, was increased 10-fold, as compared with mice infected with a control adenovirus. The findings suggest that the amino-terminal 1–202 region of apoE4 contains the domains required for the in vivo clearance of lipoprotein remnants. Furthermore, the carboxyl-terminal 203–299 residues of apoE promote hepatic very low density lipoprotein-triglyceride secretion and contribute to apoE-induced hypertriglyceridemia.