Stimulation of the in Vivo Production of Very Low Density Lipoproteins by Apolipoprotein E Is Independent of the Presence of the Low Density Lipoprotein Receptor

Apolipoprotein (apo) E stimulates the secretion of very low density lipoproteins (VLDLs) by an as yet unknown mechanism. Recently, a working mechanism for apoE was proposed (Twisk, J., Gillian-Daniel, D. L., Tebon, A., Wang, L., Barrett, P. H., and Attie, A. D. (2000) J. Clin. Invest. 105, 521-532) in which apoE prevents the inhibitory action of...

Apolipoprotein E2 (Lys146→Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides

The apolipoprotein E2 (Lys146→Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL)...

Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg158→Cys) on cholesterol levels and atherosclerosis in ApoE- deficient mice

The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the development of atherosclerosis in apoE-deficient (apoe-/-) mice was investigated by using bone marrow transplantation (BMT). At 4 weeks after BMT, murine apoe+/+ bone marrow reduced serum...

Macrophage scavenger receptor class A: A multifunctional receptor in atherosclerosis

In atherogenesis, elevated plasma levels of low density lipoprotein (LDL) lead to the chronic presence of LDL in the arterial wall. There, LDL is modified (eg, oxidized), and these modified lipoproteins activate endothelial cells, which attract circulating monocytes. These monocytes enter the vessel wall, differentiate into macrophages, and...

Very-low-density lipoprotein binding to the apolipoprotein E receptor 2 is enhanced by lipoprotein lipase, and does not require apolipoprotein E

The apolipoprotein (apo)E receptor 2 (apoER2) is a recently cloned member of the low-density lipoprotein (LDL) receptor (LDLR) family, showing a high homology with both the LDLR and the very-low-density lipoprotein (VLDL) receptor (VLDLR). In the present study, the binding characteristics of the apoER2 with respect to apoE and lipoprotein lipase...

Binding of β-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas apoE only modulates binding affinity

The binding of β-VLDL to heparan sulfate proteoglycans (HSPG) has been reported to be stimulated by both apoE and lipoprotein lipase (LPL). In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of β-VLDL to HSPG. Therefore, we isolated β-VLDL from transgenic...

Hyperlipidemia of ApoE2(Arg158-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression

To investigate the relative roles of the LDL receptor- and non-LDL receptor-mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg158-Cys) (apoE2) and apoE3- Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-...

Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice

Apolipoprotein (apo) E3Leiden is a dysfunctional apo E variant associated with familial dysbetalipoproteinemia in humans. Transgenic mice carrying the APOE3Leiden gene develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. An early step in atherosclerosis is foam cell formation, which is thought to result from the...

Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages

Macrophage scavenger receptors class A (MSR) are thought to play an important role in atherogenesis by mediating the unrestricted uptake of modified lipoproteins by macrophages in the vessel wall leading to foam cell formation. To investigate the in vivo role of the MSR in this process, a transgenic mouse model expressing both isoforms of the...

Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver

ApoE-deficient mice on low fat diet show hepatic triglyceride accumulation and a reduced very low density lipoprotein (VLDL) triglyceride production rate. To establish the role of apoE in the regulation of hepatic VLDL production, the human APOE3 gene was introduced into apoE-deficient mice by cross-breeding with APOE3 transgenics (APOE3/apoe-/-...

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes (Apoe-/- · Ldlr-/-) using adenovirus-mediated gene...

Reversal of hypercholesterolemia in apolipoprotein E2 and apolipoprotein E3-Leiden transgenic mice by adenovirus-mediated gene transfer of the VLDL receptor

We have investigated the interaction of apolipoprotein E2(Arg158- Cys) (apoE2) and apolipoprotein E3Leiden (apoE3-Leiden) with the very low density lipoprotein (VLDL) receptor in vivo and in vitro to define the possible role of this receptor in lipoprotein metabolism and atherosclerosis. The in vivo binding specificity of the VLDL receptor for...

Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice

To study the function of plasma phospholipid transfer protein (PLTP) in vivo, a liver directed adenoviral gene transfer system was used to overexpress human PLTP in mice. For the experiments, two strains of mice, wild type (C57/B1) and mice transgenic for the human apoA-I gene (HuApoA- ITg), were utilized. Five days after injection of the...

Use of transgenic mice in lipoprotein metabolism and atherosclerosis research

In APOE*3-Leiden transgenic mice the atherosclerotic lesion size is correlated with plasma cholesterol. In these mice the plasma lipid levels are positively correlated with the relative amount of APOE 3-Leiden protein on the VLDL particle. The plasma cholesterol levels are influenced by diet, age and gender, mainly due to an effect of these...

In the absence of endogenous mouse apolipoprotein E, apolipoprotein E*2(Arg-158 → Cys) transgenic mice develop more severe hyperlipoproteinemia than apolipoprotein E*3-Leiden transgenic mice

Apolipoprotein E*2(Arg-155 → Cys) (APOE*2) transgenic mice were generated and compared to the previously generated apolipoprotein E*3- Leiden (APOE*3-Leiden) transgenic mice to study the variable expression of hyperlipoproteinemia associated with these two APOE variants. In the presence of the endogenous mouse Apoe gene, the expression of the...

Genomic cloning of the mouse LDL receptor related protein/_2-macroglobulin receptor gene

The LDL receptor-related protein (LRP) or alpha 2-macroglobulin receptor (A2mr) is encoded by a 15-kb mRNA in mouse and human. Probes encompassing different regions of the mouse cDNA were used to isolate clones from a cosmid library of mouse strain 129. Four overlapping cosmids were used for restriction mapping and Southern blot analysis. This...