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Journal of Lipid Research, Vol. 43, 1520-1528, September 2002
Copyright © 2002 by Lipid Research, Inc.

ApoB-48 and apoB-100 differentially influence the expression of type-III hyperlipoproteinemia in APOE*2 mice

Myron E. Hinsdale2,1, Patrick M. Sullivan3, Hafid Mezdour4 and Nobuyo Maeda

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525

1 To whom correspondence should be sent. e-mail: myron-hinsdale{at}omrf.ouhsc.edu

Apolipoprotein E (apoE) is essential for the clearance of plasma chylomicron and VLDL remnants. The human APOE locus is polymorphic and 5–10% of APOE*2 homozygotes exhibit type-III hyperlipoproteinemia (THL), while the remaining homozygotes have less than normal plasma cholesterol. In contrast, mice expressing APOE*2 in place of the mouse Apoe (Apoe2/2 mice) are markedly hyperlipoproteinemic, suggesting a species difference in lipid metabolism (e.g., editing of apolipoprotein B) enhances THL development. Since apoB-100 has an LDLR binding site absent in apoB-48, we hypothesized that the Apoe2/2 THL phenotype would improve if all Apoe2/2 VLDL contained apoB-100. To test this, we crossed Apoe2/2 mice with mice lacking the editing enzyme for apoB (Apobec-/-). Consistent with an increase in remnant clearance, Apoe2/2 · Apobec-/- mice have a significant reduction in IDL/LDL cholesterol (IDL/LDL-C) compared with Apoe2/2 mice. However, Apoe2/2 ·Apobec-/- mice have twice as much VLDL triglyceride as Apoe2/2 mice. In vitro tests show the apoB-100-containing VLDL are poorer substrates for lipoprotein lipase than apoB-48-containing VLDL.

Thus, despite a lowering in IDL/LDL-C, substituting apoB-48 lipoproteins with apoB-100 lipoproteins did not improve the THL phenotype in the Apoe2/2 ·Apobec-/- mice, because apoB-48 and apoB-100 differentially influence the catabolism of lipoproteins.

Abbreviations: Apobec, apolipoprotein B editing complex-1 gene; Apoe2/2 mice, mice with apolipoprotein E allele APOE*2 replaced for mouse Apoe gene; FC, free cholesterol; FPLC, fast protein liquid chromatography; LDLR, low density lipoprotein receptor; LpL, lipoprotein lipase; PL, phospholipids; TC, total cholesterol; TG, triglycerides; THL, type-III hyperlipoproteinemia

Supplementary key words lipoproteins • very low density lipoprotein • metabolism • lipoprotein remnants


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