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

Abstract

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. Apolipoprotein E (apoE) is essential for the clearance of chylomicron and VLDL remnants from the plasma. Variant apoE proteins in humans are known to cause primary dysbetalipoproteinemia [or type-III hyperlipoproteinemia (THL)], which is characterized by the accumulation of chylomicron and VLDL remnants in the plasma and a high incidence of coronary artery and peripheral vessel atherosclerosis (1). The most common form of THL is associated with homozygosity for the APOE*2 allele, whose product, apoE-2, has Ͻ 2% normal binding to the low density lipoprotein receptor (LDLR) in vitro. However, the majority of APOE*2 homozygotes typically have normal to below normal plasma levels of cholesterol and triglycerides (TG) and only 5-10% of the homozygotes develop THL. Thus, reductions in lipoprotein clearance due to hormonal, dietary, and genetic changes resulting in reduced LDLR function or capacity are thought to trigger the THL (2). In support of this hypothesis, some of these THL patients have other disorders such as hyperuricemia, glucose intolerance, obesity, and hypothyroidism (3, 4). Nevertheless, the basic mechanism why only 5-10% of APOE*2 homozygotes develop THL while the remaining homozygotes have below normal cholesterol levels remains unexplained.To approach this fundamental question, we previously generated mice ( Apoe 2/2 mice) which solely express the APOE*2 allele under the control of the endogenous mouse Apoe promoter by using a gene-targeted replacement strategy (5). Surprisingly, all the Apoe 2/2 mice, regardless of age and gender, exhibit many characteristics of THL, while mice similarly made to ...

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Influence of Synthetic Antioxidants Used in Food Technology on the Bioavailability and Metabolism of Lipids - <i>In Vitro</i> Studies

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