ApoB-48 and apoB-100 differentially influence the expression of type-III hyperlipoproteinemia in APOE*2 mice.
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 (Apoe(2/2) 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 Apoe(2/2) THL phenotype would improve if all Apoe(2/2) VLDL contained apoB-100. To test this, we crossed Apoe(2/2) mice with mice lacking the editing enzyme for apoB (Apobec(-/-)). Consistent with an increase in remnant clearance, Apoe(2/2). Apobec(-/-) mice have a significant reduction in IDL/LDL cholesterol (IDL/LDL-C) compared with Apoe(2/2) mice. However, Apoe(2/2).Apobec(-/-) mice have twice as much VLDL triglyceride as Apoe(2/2) 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 Apoe(2/2).Apobec(-/-) mice, because apoB-48 and apoB-100 differentially influence the catabolism of lipoproteins.
Hinsdale
Myron E
ME
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA. myron-hinsdale@omrf.ouhsc.edu
Sullivan
Patrick M
PM
Mezdour
Hafid
H
Maeda
Nobuyo
N
D000818:Animals; D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D053329:Apolipoprotein E2; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006952:Hyperlipoproteinemia Type III / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D053329:Apolipoprotein E2; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D014280:Triglycerides