Targeted In Situ Gene Correction of Dysfunctional<i>APOE</i>Alleles to Produce Atheroprotective Plasma ApoE3 Protein

Simons, Paul; Owen, James S.

doi:10.1155/2012/148796

Cited by 12 publications

(16 citation statements)

References 152 publications

(171 reference statements)

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“…As indicated earlier, differential binding affinities of the individual ApoE isoforms to receptors and for surfaces of triglyceride-rich lipoprotein particles underlie such variation [16], [18]. We also noted effects of APOE genotype on TC and LDL-C in our controls as mean values were significantly lower in ε2-carriers compared to the ε3/ε3 group ( P = 0.0052 and P = 0.0157, respectively), though unchanged for the ε4-allele.…”

Section: Discussionsupporting

confidence: 76%

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

et al. 2014

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BackgroundSchistosomiasis mansoni is a parasitic liver disease, which causes several metabolic disturbances. Here, we evaluate the influence of Apolipoprotein E (APOE) gene polymorphism, a known modulator of lipid metabolism, on plasma lipid levels in patients with hepatosplenic schistosomiasis.Methodology/Principal FindingsBlood samples were used for APOE genotyping and to measure total cholesterol (TC), LDL-C, HDL-C and triglycerides. Schistosomiasis patients had reduced TC, LDL-C and triglycerides (25%, 38% and 32% lower, respectively; P<0.0001) compared to control individuals, whereas HDL-C was increased (10% higher; P = 0.0136). Frequency of the common alleles, ε2, ε3 and ε4, was similar (P = 0.3568) between controls (n = 108) and patients (n = 84), implying that APOE genotype did not affect susceptibility to the advanced stage of schistosomiasis. Nevertheless, while patient TC and LDL-C levels were significantly reduced for each allele (except TC in ε2 patients), changes in HDL-C and triglycerides were noted only for the less common ε2 and ε4 alleles. The most striking finding, however, was that accepted regulation of plasma lipid levels by APOE genotype was disrupted by schistosomiasis. Thus, while ε2 controls had higher TC and LDL-C than ε3 carriers, these parameters were lower in ε2 versus ε3 patients. Similarly, the inverse relationship of TG levels in controls (ε2>ε3>ε4) was absent in patients (ε2 or ε4>ε3), and the increase in HDL-C of ε2 or ε4 patients compared to ε3 patients was not seen in the control groups.Conclusion/SignificanceWe confirm that human schistosomiasis causes dyslipidemia and report for the first time that certain changes in plasma lipid and lipoprotein levels depend on APOE gene polymorphism. Importantly, we also concluded that S. mansoni disrupts the expected regulation of plasma lipids by the different ApoE isoforms. This finding suggests ways to identify new metabolic pathways affected by schistosomiasis and also potential molecular targets to treat associated morbidities.

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Section: Discussionsupporting

confidence: 76%

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

et al. 2014

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“…This bridge could disrupt receptor binding because Arg150 is part of the LDL binding site. 27 This mutation was related to type III hyperlipoproteinemia (HLP). 6 Exchange of Asp154 to an alanine could induce the disruption of the Arg150 and Asp154 bridge, and the receptor-binding activity could return to the normal level.…”

Section: Importance Of Apoementioning

confidence: 99%

Role of apolipoprotein E in neurodegenerative diseases

Giau¹,

Bagyinszky²,

An³

et al. 2015

NDT

138

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Apolipoprotein E (APOE) is a lipid-transport protein abundantly expressed in most neurons in the central nervous system. APOE-dependent alterations of the endocytic pathway can affect different functions. APOE binds to cell-surface receptors to deliver lipids and to the hydrophobic amyloid-β peptide, regulating amyloid-β aggregations and clearances in the brain. Several APOE isoforms with major structural differences were discovered and shown to influence the brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review will summarize the updated research progress on APOE functions and its role in Alzheimer’s disease, Parkinson’s disease, cardiovascular diseases, multiple sclerosis, type 2 diabetes mellitus, Type III hyperlipoproteinemia, vascular dementia, and ischemic stroke. Understanding the mutations in APOE, their structural properties, and their isoforms is important to determine its role in various diseases and to advance the development of therapeutic strategies. Targeting APOE may be a potential approach for diagnosis, risk assessment, prevention, and treatment of various neurodegenerative and cardiovascular diseases in humans.

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“…The low density lipoprotein receptor (LDLR) is located on the short arm of the same chromosome, suggesting chromosome 19 to play an important role in lipoprotein metabolism [ 35 ]. The APOE gene is composed of four exons, separated by three introns [ 36 ]. The mature APOE protein found in plasma is 299 amino acids long (Molecular weight ~34000 Dalton).…”

Section: Introductionmentioning

confidence: 99%

APOE genotype and stress response - a mini review

et al. 2016

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The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age-related diseases, including cardiovascular and Alzheimer’s disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype.

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Targeted In Situ Gene Correction of DysfunctionalAPOEAlleles to Produce Atheroprotective Plasma ApoE3 Protein

Cited by 12 publications

References 152 publications

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

Role of apolipoprotein E in neurodegenerative diseases

APOE genotype and stress response - a mini review

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