Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo - Carboxyl-terminal region 203-299 promotes hepatic verylow density lipoprotein-triglyceride secretion

Apolipoprotein (apo)E has been implicated in cholesterol. and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficie nt clearance of apoE-containing lipoprotein remnants. However, high apoE pl asma levels correlate with high plasma triglyceride levels. We have used ad enovirus-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 x 10(9) plaque-forming units of apoE4-expressing adenovir us reduced slightly the cholesterol levels of E-/- mice and resulted in sev ere hypertriglyceridemia, due to accumulation of cholesterol and triglyceri de-rich very low density Lipoprotein particles in plasma, In contrast, the truncated form apoE4-202 resulted in a 90% reduction in the plasma choleste rol levels but did not alter plasma triglyceride levels in the E-/- mice. A poE secretion by cell cultures, as well as the steady-state hepatic mRNA le vels in individual mice expressing apoE4 or apoE4-202, were similar. In con trast, very low density lipoprotein-triglyceride secretion in mice expressi ng apoE4, but not, apoE4-202, was increased 10-fold, as compared with mice infected with a control adenovirus, The findings suggest that the amino-ter minal 1-202 region of apoE4 contains the domains required for the in vivo c learance of Lipoprotein remnants. Furthermore, the carboxyl-terminal 203-29 9 residues of apoE promote hepatic very low density lipoprotein-triglycerid e secretion and contribute to apoE-induced hypertriglyceridemia.