Apolipoprotein A-V

Vliet, Hendrik N. van der; Sammels, Martijn Groenink; Leegwater, A. C.; Levels, J.H.M.; Reitsma, Pieter H.; Boers, W.; Chamuleau, R. A. F. M.

doi:10.1074/jbc.m106888200

Cited by 249 publications

(92 citation statements)

References 45 publications

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“…suggests human apoA-V may exist in association with lipoproteins in the plasma compartment, consistent with its observed plasma distribution in animal models (6,7). Based on the fact that apoA-V is a member of the apoA-I/CIII/A-IV gene family whose protein products belong to the exchangeable apolipoprotein family, studies were conducted to characterize apoA-V in the lipid- (24,25).…”

Section: Discussionmentioning

confidence: 75%

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

et al. 2003

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To investigate structure and function relations of a new member of the exchangeable apolipoprotein family that modulates plasma lipid levels, recombinant human apolipoprotein (apo) A-V was produced in Escherichia coli and isolated by a combination of nickel chelation affinity chromatography and reversed-phase HPLC. Antibodies directed against apoA-V were generated and employed in immunoblotting experiments. Anti-apoA-V IgG gave a strong response against recombinant apoA-V from E. coli and human apoA-V expressed in transgenic mice, but did not recognize human apoA-I or apoA-IV. In neutral-pH buffers, at concentrations of >0.1 mg/mL, isolated lipid-free apoA-V is poorly soluble. By contrast, apoA-V is soluble in 50 mM sodium citrate (pH 3.0). Far-UV circular dichroism analysis and spectral deconvolution reveal that apoA-V possesses 32% α-helix, 33% β-sheet, 16% β-turn, and 18% random coil secondary structure conformers. Temperature-induced denaturation studies gave rise to a transition midpoint of 47.1 °C. Upon being cooled to ambient temperature from 85 °C, apoA-V failed to recover all of the negative ellipticity present in unheated apoA-V. ApoA-V interacts with bilayer vesicles of dimyristoylphosphatidylcholine to form discoidal complexes with diameters in the range of 15−20 nm. However, apoA-V was a poor activator of lecithin:cholesterol acyltransferase where the activity was 8.5 ± 1.8% of that of apoA-I. Furthermore, apoA-V failed to support enhanced efflux of cholesterol from cAMP-treated J774 macrophages, although low levels of efflux were obtained from unstimulated cells. Taken together, the results demonstrate recombinant apoA-V possesses unique structural and functional characteristics, in keeping with its proposed role in the modulation of plasma lipid levels.

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Section: Discussionmentioning

confidence: 75%

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

et al. 2003

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“…Preparation of Recombinant ApoAV-Rat apoAV protein was produced by transformed Escherichia coli BL21(DE3) cells as described previously (3). The N-terminally hexahistidine-tagged apoAV protein was purified from guanidinium hydrochloride-solubilized inclusion bodies by metal affinity chromatography (AP Biotech) using an fast protein liquid chromatography system.…”

Section: Materials-glycerolmentioning

confidence: 99%

“…Hereto, 50-l samples were added to 1.5 ml of CH 3 OH:CHCl 3 : heptane:oleic acid (1410:1250:1000:1 (v/v/v/v)) and to 0.5 ml of 0.2 M NaOH. Following vigorous mixing and centrifugation (10 min at 1000 ϫ g), 3 H radioactivity in 0.5 ml of the aqueous phase was counted in 5 ml of Ultima Gold (Packard Bioscience). The recovery of [ 3 H]oleate in the aqueous phase following organic extraction was corrected for a 78.0 Ϯ 0.9% recovery of [1-14 C]oleate internal standard.…”

Section: Materials-glycerolmentioning

confidence: 99%

“…At present, it is unknown in what form apoAV is secreted by the liver. The circulating mature form has a predicted molecular mass of 39 kDa and is associated mainly with HDL and to a lesser extent with VLDL particles (3). This distribution is somewhat puzzling as apoAV mainly seems to affect VLDL metabolism.…”

mentioning

confidence: 99%

“…Recently, a novel apolipoprotein, apoAV, has been identified that strongly influences plasma triglyceride (TG) levels (2,3). The human APOA5 gene is part of the apolipoprotein gene cluster on chromosome 11q23 that also encompasses APOA1, APOC3, and APOA4.…”

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confidence: 99%

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ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis

Schaap¹,

Rensen

Voshol

et al. 2004

Journal of Biological Chemistry

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275

247

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ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 ؋ 10 8 plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29 -37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68 -88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.Hypertriglyceridemia is a risk factor for coronary heart disease independent from the well known risk factors such as elevated LDL 1 and reduced HDL cholesterol levels (1). Recently, a novel apolipoprotein, apoAV, has been identified that strongly influences plasma triglyceride (TG) levels (2, 3). The human APOA5 gene is part of the apolipoprotein gene cluster on chromosome 11q23 that also encompasses APOA1, APOC3, and APOA4. An initial study revealed the association of three single nucleotide polymorphisms within the APOA5 locus with plasma TG levels and VLDL mass in humans (2). Importantly, these metabolic effects were not associated with a genetic marker in the nearby APOC3 gene that is also known to affect plasma TG levels (2). Subsequent studies in diverse ethnic groups uncovered additional single nucleotide polymorphisms including apoAV protein variants and further supported a role for common genetic variations in APOA5 in influencing plasma TG levels (4, 5). Interestingly, in a recent study, minor allele frequencies of 3 of 5 studied single nucleotide polymorphisms were found to be significantly higher in a hypertriglyceridemic population (4).Mouse models confirmed the TG-modulating effects of apoAV observed in humans. Mice expressing a human APOA5 transgene showed a 65% decrease in plasma TG levels compared with control mice (2). Conversely, apoa5 knock-out mice showed a 400% increase in plasma TG concentration (2). Interestingly, the adenovirus-mediated expression of apoAV in mice resulted in a decrease of b...

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Lipid and Lipoprotein Metabolism

Pullinger

Kane

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Apolipoprotein A-V

Cited by 249 publications

References 45 publications

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

Structure−Function Studies of Human Apolipoprotein A-V: A Regulator of Plasma Lipid Homeostasis

ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis

Lipid and Lipoprotein Metabolism

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