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Allele-dependent thermodynamic and structural perturbations in ApoE variants associated with the correction of dyslipidemia and formation of spherical ApoE-containing HDL particles.

ABSTRACT: Overexpression of ApoE4[Leu261Ala/Trp264Ala/Phe265Ala] mutant (ApoE4mutC) prevents hypertriglyceridemia and promotes formation of spherical ApoE-containing HDL in ApoE(-/-) or ApoA-I(-/-) mice. Although, a similar phenotype was observed with ApoE2[Leu261Ala/Trp264Ala/Phe265Ala] (ApoE2mutC), small differences in cholesterol distribution to IDL/LDL, HDL2 and HDL3 fractions and ApoE distribution to HDL2 and HDL3 fractions suggested that ApoE allelic background can influence mutant ApoE properties. To understand the structural basis behind the properties of ApoE2mutC and ApoE4mutC variants we analyzed their structural and thermodynamic integrity in comparison to their wild-type counterparts. Circular dichroism spectroscopy revealed a significantly reduced helical content for both mutants compared to wild-type. The presence of mutation only marginally affected the thermal stability of ApoE4 but greatly affected the thermal stability profile of ApoE2 leading to a previously uncharacterized intermediate stage. Both ApoE4mutC and ApoE2mutC were slightly stabilized against chemical denaturation compared to their wild-type counterparts. ApoE2mutC, in contrast to ApoE4mutC, exposed a larger hydrophobic surface to the solvent as determined by a fluorescent probe. Both mutants remodeled 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles with identical kinetics to the wild-type proteins. Given the known conformational differences between ApoE2 and ApoE4, our findings suggest that the 261-265 region may be involved in inter-domain interactions within the ApoE molecule. Overall, we show that substitution of Leu261, Trp264 and Phe265 with Ala in ApoE2 leads to more pronounced perturbations of thermodynamic stability and structure than in ApoE4. The minimal perturbations in ApoE4mutC may make it a more suitable candidate for therapeutic applications for the correction of remnant removal disorders and atheroprotection.

SUBMITTER: Georgiadou D

PROVIDER: S-EPMC3546125 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Allele-dependent thermodynamic and structural perturbations in ApoE variants associated with the correction of dyslipidemia and formation of spherical ApoE-containing HDL particles.

Georgiadou Dimitra D Chroni Angeliki A Drosatos Konstantinos K Kypreos Kyriakos E KE Zannis Vassilis I VI Stratikos Efstratios E

Atherosclerosis 20121123 2

Overexpression of ApoE4[Leu261Ala/Trp264Ala/Phe265Ala] mutant (ApoE4mutC) prevents hypertriglyceridemia and promotes formation of spherical ApoE-containing HDL in ApoE(-/-) or ApoA-I(-/-) mice. Although, a similar phenotype was observed with ApoE2[Leu261Ala/Trp264Ala/Phe265Ala] (ApoE2mutC), small differences in cholesterol distribution to IDL/LDL, HDL2 and HDL3 fractions and ApoE distribution to HDL2 and HDL3 fractions suggested that ApoE allelic background can influence mutant ApoE properties. ...[more]

PMID: 23228878

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Project description:Background and purposeATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.MethodsMiddle-aged male specific brain ABCA1-deficient (ABCA1-B/-B) and floxed-control (ABCA1fl/fl) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1-B/-B stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.ResultsNo differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1fl/fl ischemic mice, ABCA1-B/-B ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1-B/-B ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-B/-B-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1-B/-B embryos.ConclusionsABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.

Dataset Information

Allele-dependent thermodynamic and structural perturbations in ApoE variants associated with the correction of dyslipidemia and formation of spherical ApoE-containing HDL particles.

Publications

Allele-dependent thermodynamic and structural perturbations in ApoE variants associated with the correction of dyslipidemia and formation of spherical ApoE-containing HDL particles.

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