Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E

Wilson, Charles B.; Wardell, Mark R.; Weisgraber, Karl H.; Mahley, Robert W.; Agard, David A.

doi:10.1126/science.2063194

Cited by 674 publications

(582 citation statements)

References 40 publications

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“…ApoE is also expressed in other tissues, notably the brain, which is a prolific tissue in terms of apoE production [8,24]. As a key determinant of plasma cholesterol homeostasis, apoE, a 299-amino acid secretory protein, binds with high affinity to lipoprotein particles in the plasma compartment and acts as a ligand for receptormediated endocytosis via multiple members of the low-density lipoprotein receptor family [1,25].…”

Section: Discussionmentioning

confidence: 99%

“…Representative hematoxylin and eosin histology (original magnification ×100) of distal ileal sections from the experimental mice at day 27 after weaning and refeeding. Blunted expression of IGF-1 in the ileum mucosa from malnourished apoE null mice at day 27 (B and D), after the refeeding protocol (day [21][22][23][24][25][26][27], in comparison with the rehabilitated malnourished wild-type controls (A and C), using immunoblotting and immunohistochemistry, respectively. Distal ileum sections were used at 200× magnification for panels C and D. Insulinlike growth factor α receptor expression from distal ileal sections (original magnification ×100).…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

et al. 2006

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Apolipoprotein E (apoE) is synthesized mainly in the liver and in the brain and is critical for cholesterol metabolism and recovery from brain injury. However, although apoE mRNA increases at birth, during suckling, and after fasting in rat liver, little is known about its role in early postnatal development. Using an established postnatal malnutrition model and apoE knock-out (ko) mice, we examined the role of apoE in intestinal adaptation responses to early postnatal malnutrition. Wild-type and apoE-ko mice were separated from their lactating dams for defined periods each day (4 hours on day 1, 8 hours on day 2, and 12 hours thereafter). We found significant growth deficits, as measured by weight gain or tail length, in the apoE-ko mice submitted to a malnutrition challenge, as compared with malnourished wild type, especially during the second week of postnatal development (P < .05). In addition, apoE-ko animals failed to show growth catch-up after refeeding, compared with wild-type malnourished controls. Furthermore, we found shorter crypts and reduced villus height and area in the apoE-ko malnourished mice, compared with controls, after refeeding. Insulinlike growth factor 1 expression was also blunted in the ileum in apoE-ko mice after refeeding, compared with wild-type controls, which exhibited full insulinlike growth factor 1 expression along the intestinal crypts, villi, and in the muscular layer. Taken together, these findings suggest the importance of apoE in coping with a malnutrition challenge and during the intestinal adaptation after refeeding. NIH Public Access

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

et al. 2006

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“…Helix 1 pairs with helix 2, and helix 3 with helix 4, arranged in an antiparallel mode, with the hydrophobic faces oriented towards the interior of the bundle (Wilson et al 1991). ApoE genotype impacts on the three-dimensional orientation of the apoE regions and amino-terminal-carboxyl-terminal interactions, which affect receptor binding and lipoprotein apoE distribution, as will be discussed (see pp.…”

Section: Apoe Structure and Tissue Sourcesmentioning

confidence: 95%

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

et al. 2007

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Cardiovascular risk is determined by the complex interactions between genetic and environmental factors. The apoE genotype represents the most-widely-studied single nucleotide polymorphism in relation to CVD risk, with > 3600 publications cited in PubMed. Although originally described as a mediator of lipoprotein metabolism, the lipoprotein-independent functions of apoE are being increasingly recognised, with limited data available on the potential impact of genotype on these metabolic processes. Furthermore, although meta-analyses suggest that apoE4 carriers may have a 40-50% increased CVD risk, the associations reported in individual studies are highly heterogeneous and it is recognised that environmental factors such as smoking status and dietary fat composition influence genotype-phenotype associations. However, information is often derived from observational studies or small intervention trials in which retrospective genotyping of the cohort results in small group sizes in the rarer E2 and E4 subgroups. Either larger well-standardised intervention trials or smaller trials with prospective recruitment according to apoE genotype are needed to fully establish the impact of diet on genotype-CVD associations and to establish the potential of dietary strategies such as reduced total fat, saturated fat, or increased antioxidant intakes to counteract the increased CVD burden in apoE4 carriers. ApoE genotype: CVD: Dietary fat: Oxidative status: InflammationThe impact of single nucleotide polymorphisms on risk of chronic diseases such as CVD, and the ability of dietary factors to manipulate genotype-phenotype associations, is being increasingly recognised. Undoubtedly, the mostwidely-studied gene variant in relation to CVD is the apoE e (e2, e3, e4) genotype. Since its discovery in 1973 the central role of the apoE protein in lipoprotein metabolism has been comprehensively investigated and reported. The 40-50 % higher risk of CVD in apoE4 carriers (Song et al. 2004) has been traditionally attributed to moderately higher circulating cholesterol and TAG levels. However, it is becoming increasingly recognised that an effect on lipoprotein metabolism alone cannot explain the disease differential and that the impact of an apoE4 genotype is largely lipoprotein independent. Roles of macrophagederived apoE protein on vascular health and atherogenesis are being identified, with apoE thought to impact on oxidative status and in an autocrine and paracrine manner affect macrophage, vascular smooth muscle cell, endothelial cell and platelet function. An impact of genotype on these localised functions of apoE could in part explain the impact of genotype on CVD pathology, as will be discussed.Additionally, apoE genotype has been shown to affect the responsiveness to the total fat content and fatty acid composition of the diet. Manipulation of dietary fat content may serve as a means of reducing the increased CVD burden associated with an apoE4 genotype.

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“…ApoE contains 299 amino acids and is comprised of two structural domains, a 22 kDa N-terminal (NT) domain and a 10 kDa C-terminal domain [3]. In the absence of lipid the NT domain is organized as a four-helix bundle [4]. Each of the four helices are amphipathic and orient their non polar face toward the interior of the bundle, forming a leucine zipper type motif.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor

Yamamoto¹,

Choi²,

Ryan³

2008

Analytical Biochemistry

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Apolipoprotein E (apoE) is a ligand for members of the low-density lipoprotein receptor (LDLR) family and functions in plasma cholesterol homeostasis. A fluorescence-based assay has been employed in molecular studies of receptor-ligand interactions. Competition experiments revealed isoform specific differences in binding of lipid-associated apoE N terminal (NT) domain to a recombinant soluble LDLR (sLDLR). In a similar manner, lipid associated, but not lipid-free, fulllength apoE3 showed binding activity to sLDLR. The molecular chaperone, Receptor Associated Protein, inhibited apoE3-NT-phospholipid complex binding to sLDLR. Kinetic studies of apoE3-NT-phospholipid complex interaction with sLDLR revealed time dependent effects of apoE-NT isoform binding to sLDLR. The results reveal a discerning method for study of the molecular basis of ligand interactions that likely influence receptor function in maintenance of whole body cholesterol homeostasis.

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Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E

Cited by 674 publications

References 40 publications

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor

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