Apo E structure determines VLDL clearance and atherosclerosis risk in mice.
We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.
Knouff
C
C
Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7525, USA.
Hinsdale
M E
ME
Mezdour
H
H
Altenburg
M K
MK
Watanabe
M
M
Quarfordt
S H
SH
Sullivan
P M
PM
Maeda
N
N
D000818:Animals; D001011:Aorta / Q000473:pathology; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012307:Risk Factors
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL