title: Apo E structure determines VLDL clearance and atherosclerosis risk in mice.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599-7525, USA.
authors.forename: C
authors.initials: C
authors.lastname: Knouff
authors.forename: M E
authors.initials: ME
authors.lastname: Hinsdale
authors.forename: H
authors.initials: H
authors.lastname: Mezdour
authors.forename: M K
authors.initials: MK
authors.lastname: Altenburg
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: S H
authors.initials: SH
authors.lastname: Quarfordt
authors.forename: P M
authors.initials: PM
authors.lastname: Sullivan
authors.forename: N
authors.initials: N
authors.lastname: Maeda
mesh_terms: 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
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL