Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxyl-terminal region 203-299 promotes hepatic very low density lipoprotein-triglyceride secretion.
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 x 10(9) 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.
Kypreos
K E
KE
Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
van Dijk
K W
KW
van Der Zee
A
A
Havekes
L M
LM
Zannis
V I
VI
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002853:Chromatography, Liquid; D017931:DNA Primers; D005260:Female; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D017931:DNA Primers; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol