Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner

Jong, C. M. De; Dahlmans, E. H. Vivian; Hofker, H. Marten; Havekes, M. Louis

doi:10.1042/bj3280745

Cited by 54 publications

(49 citation statements)

References 31 publications

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“…This appears to be a major reason for the TG increase because there is no difference in TG secretion rates between the Apoe 2/2 ·Apobec Ϫ/Ϫ and Apoe 2/2 mice. Increases in apoE plasma levels can have a dose dependent inhibition on LpL activity (25)(26)(27)(28). However, we found the Apoe 2/2 · Apobec Ϫ/Ϫ mice have similar amounts of plasma and VLDL apoE-2 as compared with the Apoe 2/2 mice, which excludes the levels of apoE-2 as a cause for decrease in VLDL lipolysis.…”

Section: Discussioncontrasting

confidence: 52%

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

Hinsdale¹,

Sullivan²,

Mezdour³

et al. 2002

Journal of Lipid Research

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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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Section: Discussioncontrasting

confidence: 52%

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

Hinsdale¹,

Sullivan²,

Mezdour³

et al. 2002

Journal of Lipid Research

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“…24 -26 However, this negative effect on triglyceride lipolysis may be partly apoE isotype independent, because wild-type apoE3 can also decrease the efficiency of triglyceride lipolysis when present at high levels on the VLDL. 23,[27][28][29][30] On the basis of our experiments, we cannot distinguish quantitative effects from qualitative effects of apoE2 and apoE3-Leiden on the efficiency of triglyceride lipolysis. It has recently been described that increased levels of mouse apoE in the serum of ApoeϪ/Ϫ.LdlrϪ/Ϫ mice do not result in hypertriglyceridemia.…”

Section: Discussionmentioning

confidence: 90%

Hyperlipidemia of ApoE2(Arg ₁₅₈ -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

Dijk

Vlijmen

Winther

et al. 1999

ATVB

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Abstract-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(Arg 158 -Cys) (apoE2) and apoE3-Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (ApoeϪ/Ϫ.LdlrϪ/Ϫ mice). Unexpectedly, on the ApoeϪ/Ϫ.LdlrϪ/Ϫ background, expression of neither apoE2 nor apoE3-Leiden results in a decrease of the hyperlipidemia. In contrast, serum cholesterol levels are increased by the introduction of apoE2 and apoE3-Leiden in ApoeϪ/Ϫ.LdlrϪ/Ϫ mice (to 39.1Ϯ7.1 and 37.6Ϯ7.6 mmol/L, respectively, from 25.9Ϯ6.5 mmol/L). In addition, in these transgenic mice, the serum triglyceride levels are substantially increased (to 9.6Ϯ7.0 and 5.8Ϯ2.8 mmol/L, respectively, from 0.7Ϯ0.5 mmol/L), which is associated with a decreased efficiency of in vitro LPL-mediated lipolysis of circulating VLDL. The VLDL-triglyceride secretion rate is not affected by the expression of apoE2 or apoE3-Leiden on the ApoeϪ/Ϫ.LdlrϪ/Ϫ background. These results indicate that in the absence of the LDL receptor, clearance of triglyceride-rich apoE2 and apoE3-Leiden-containing lipoproteins via alternative hepatic receptors, such as the LDL receptor-related protein (LRP) is inefficient. Although apoE2 and apoE3-Leiden are disturbed in binding to the LDL receptor in vitro, expression of 1 or 2 mouse Ldlr alleles in an apoE2.ApoeϪ/Ϫ or apoE3-Leiden.ApoeϪ/Ϫ background results in a gene dose-dependent decrease of the hyperlipidemia. Furthermore, overexpression of the LDL receptor via adenovirus-mediated gene transfer rescues the hyperlipidemia associated with apoE2 and apoE3-Leiden expression. These data indicate that in apoE2 and apoE3-Leiden transgenic mice, the LDL receptor constitutes the predominant route for clearance of VLDL remnants, carrying even poorly binding apoE variants, and that this pathway is functional despite an apoE-mediated disturbance in VLDL triglyceride lipolysis. Key Words: apolipoprotein E Ⅲ LDL receptor Ⅲ LDL receptor-related protein Ⅲ hypertriglyceridemia Ⅲ VLDL triglyceride lipolysis A polipoprotein (apo) E plays a key role in the lipoprotein metabolism by functioning as a ligand for receptormediated uptake of chylomicron and VLDL remnants by the liver (for review, see Reference 1). Mutations in apoE are associated with familial dysbetalipoproteinemia (FD), which is characterized by elevated levels of chylomicron and VLDL remnants in the serum and premature atherosclerosis (for reviews, see References 2 and 3). Several variant forms of apoE leading to FD have been described, such as the common apoE2(Arg 158 -Cys) (apoE2) variant, which is inherited as a recessive trait, and the rare apoE3-Leiden variant, which is inherited as a dominant trait. 4 The penetrance and severity of FD associated with the apoE2 and apoE3-Leiden variants is variable, 1,4 most likely because of the genetic and environmental heterogeneity of the human population. To investigate the role of these apoE variants in FD in a...

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“…This is likely caused by a delayed lipoprotein clearance that is due to the presence of APOE3Leiden in high concentrations and a consequently decreased hydrolysis of VLDL-TG. Jong et al 38 have shown that high concentrations of apoE inhibit lipolysis, probably by steric hindrance of lipoprotein binding to heparan sulfate proteoglycans. Reduced lipolysis of TG-rich particles in APOE3Leiden transgenic mice in the presence of mouse apoe 18 is probably due to the lower binding affinity of APOE3Leiden to heparan sulfate proteoglycans.…”

Section: Discussionmentioning

confidence: 99%

Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion

Mensenkamp

Teusink²,

Baller³

et al. 2001

ATVB

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Abstract-Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and show impaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. These effects are normalized on the introduction of the human APOE3 gene. To assess whether this apoE effect is isoform specific, we studied hepatic lipid metabolism in mice expressing either APOE3 or the mutant APOE3Leiden on apoeϪ/Ϫ or apoeϩ/Ϫ backgrounds. The transgenes were expressed mainly in periportal hepatocytes, as revealed by in situ hybridization. Mice expressing APOE3Leiden, on the apoeϪ/Ϫ and apoeϩ/Ϫ backgrounds, had fatty livers, which were absent in APOE3/apoeϪ/Ϫ mice. APOE3Leiden/apoeϪ/Ϫ mice showed a strongly reduced VLDL-TG secretion compared with APOE3/apoeϪ/Ϫ mice (48Ϯ14 versus 82Ϯ10 mol/kg per hour, respectively). The presence of a single mouse apoe allele increased VLDL-TG secretion in APOE3Leiden/apoeϩ/Ϫ mice (121Ϯ43 mol/kg per hour) compared with APOE3Leiden/apoeϪ/Ϫ mice. These results show that APOE3Leiden does not prevent development of a fatty liver and does not normalize VLDL-TG secretion in mice with an apoE-deficient background. The presence of a single mouse apoe allele is sufficient to normalize the APOE3Leiden-associated reduction of VLDL-TG secretion but does not prevent steatosis. We conclude that apoE-mediated stimulation of VLDL secretion is isoform specific. A polipoprotein E is a constituent of VLDLs, chylomicrons, and HDLs and is essential for receptor-mediated uptake of remnant lipoproteins. 1 ApoE deficiency in mice leads to elevated plasma cholesterol levels that are due to the accumulation of remnant lipoproteins, 2-4 and apoE deficiency is associated with the development of atherosclerosis. 3 In addition, these mice develop a fatty liver when fed normal chow 5 and show a decreased VLDL-triglyceride (TG) secretion. 4 Recently, we demonstrated that the introduction of human APOE3 in apoE-deficient mice increases VLDL-TG secretion. 6 A role of apoE in control of VLDL-TG secretion in animals and cultured cells has also recently been confirmed by other groups. 7-9 It has recently been shown that humans with the APOE2/E2 genotype have a decreased VLDL secretion compared with secretion in subjects with the APOE3/E3 genotype. 10 In addition, it has been reported that VLDL-apoB secretion is decreased by 30% in humans with the APOE3/E4 genotype compared with those with the APOE3/E3 genotype. 11 In humans, the mutant APOE3Leiden isoform is associated with a dominantly inherited form of familial dysbetalipoproteinemia. 12-14 The APOE3Leiden gene contains a tandem repeat of codons 120 to 126, yielding a protein of 306 amino acids. 12,13 Transgenic mice expressing APOE3Leiden develop hyperlipidemia because of defective binding of E3Leiden-containing remnant lipoproteins to the LDL receptor and to the LDL receptor-related protein and are susceptible to diet-induced atherosclerosis. 15 We have shown recently that mice overexpressing APOE3Leiden in the presence of human APOC-I and the endogenous mouse apoe gene display hepatic lip...

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Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner

Cited by 54 publications

References 31 publications

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

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

Hyperlipidemia of ApoE2(Arg ₁₅₈ -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion

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Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner

Cited by 54 publications

References 31 publications

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

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

Hyperlipidemia of ApoE2(Arg 158 -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion

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Hyperlipidemia of ApoE2(Arg ₁₅₈ -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression