Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

Dallinga‐Thie, Geesje M.; Tol, Arie van; Hashimoto, Hiroaki; Zee, Leonie C. van Vark-van der; Jansen, Hans; Sijbrands, Eric J.G.

doi:10.1007/s00125-006-0261-0

Cited by 79 publications

(64 citation statements)

References 37 publications

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“…The BHS is a very comprehensively phenotyped resource, with the selected cohort having been followed up on average four times over 21 years with multiple metabolic measures, and thus was well-suited to addressing the aim of this study. Our cross-sectional association analyses confirmed previous findings of associations between the GCK rs1799884 variant and raised fasting glucose levels [9,22], the APOA5 rs662799 and rs3135506 variants and raised triacylglycerol levels [16,17,34], and the LPL rs328 variant and reduced triacylglycerol levels and raised HDL-C levels [20,21].…”

Section: Resultssupporting

confidence: 89%

“…The variants selected were the apolipoprotein A-V (APOA5) single nucleotide polymorphisms (SNPs) rs662799 and rs3135506; the lipoprotein lipase (LPL) SNP rs328; and the glucokinase (GCK) SNP rs1799884, which have been shown in multiple cross-sectional studies to be associated with triacylglycerol (APOA5 and LPL) [16][17][18][19][20][21], HDL-C (LPL) [20,21] and fasting glucose (GCK) [9,22] levels, traits important in the risk of diabetes and cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

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The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

et al. 2008

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Aims/hypothesis Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. Methods The individuals analysed were participants in the Busselton Health Survey (n=4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n=2,864) used linear mixed-effects models. Results The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p=0.0003 and p<0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p=0.0004) and raised HDL-C levels (p=0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p=0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p=0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p=0.0007).Conclusions/interpretation The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

et al. 2008

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“…ApoA-V in circulation, which has probably left the liver as a component of nascent VLDL, might represent a minor fraction of the overall apoA-V pool. We speculate that this cosecretion could explain the positive relationship between apoA-V levels in human plasma and plasma TG levels (16,17). Based on past and present findings, circulating apoA-V-containing lipoproteins are likely to be recognized by receptors, including heparan sulfate proteoglycans, and thereby rapidly removed.…”

Section: Discussionsupporting

confidence: 55%

“…Another as yet unexplained observation is that apoA-V levels in human plasma are positively correlated with plasma TG levels (16,17).…”

mentioning

confidence: 99%

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

Nilsson

Christensen

Raarup

et al. 2008

Journal of Biological Chemistry

103

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Apolipoprotein A-V (apoA-V) is present in low amounts in plasma and has been found to modulate triacylglycerol levels in humans and in animal models. ApoA-V displays affinity for members of the low density lipoprotein receptor (LDL-R) gene family, known as the classical lipoprotein receptors, including LRP1 and SorLA/LR11. In addition to LDL-A binding repeats, the mosaic receptor SorLA/LR11 also possesses a Vps10p domain. Here we show that apoA-V also binds to sortilin, a receptor from the Vsp10p domain gene family that lacks LDL-A repeats. Binding of apoA-V to sortilin was competed by neurotensin, a ligand that binds specifically to the Vps10p domain. To investigate the biological fate of receptor-bound apoA-V, binding experiments were conducted with cultured human embryonic kidney cells transfected with either SorLA/LR11 or sortilin. Compared with nontransfected cells, apoA-V binding to SorLA/ LR11-and sortilin-expressing cells was markedly enhanced. Internalization experiments, live imaging studies, and fluorescence resonance energy transfer analyses demonstrated that labeled apoA-V was rapidly internalized, co-localized with receptors in early endosomes, and followed the receptors through endosomes to the trans-Golgi network. The observed decrease of fluorescence signal intensity as a function of time during live imaging experiments suggested ligand uncoupling in endosomes with subsequent delivery to lysosomes for degradation. This interpretation was supported by experiments with 125 I-labeled apoA-V, demonstrating clear differences in degradation between transfected and nontransfected cells. We conclude that apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains and that apoA-V is internalized into cells via these receptors. This could be a mechanism by which apoA-V modulates lipoprotein metabolism in vivo.APOA5 is localized in the apolipoprotein APOA4/APOC3/ APOA1 gene cluster on human chromosome 11q23 (1). Transgenic mice expressing human apolipoprotein A-V (apoA-V) have decreased plasma triacylglycerol (TG) 2 levels, whereas APOA5 knock-out mice show increased plasma TG levels. Genetic variation in the human APOA5 locus correlate with changes in plasma lipoprotein levels (2-4), and a common polymorphism in APOA5 is significantly associated with increased risk for the metabolic syndrome (5, 6). Mutations in the APOA5 gene, leading to truncated apoA-V devoid of lipidbinding domains, have been demonstrated to cause severe hyperlipidemia if present in patients in the homozygous state (7).The mechanism whereby apoA-V exerts its effect on plasma TG levels is unknown. Animal studies and in vitro experiments have given rise to two different hypotheses for the function of apoA-V in vivo, inhibition of VLDL-TG production (8) or modulation of lipoprotein lipase (LPL) activity (8 -11). Adenovirusmediated gene transfer of human apoA-V into apoE-deficient mice decreased plasma TG levels as well as total plasma cholesterol levels without affecting LPL activity (12). In vitro experiments support a role fo...

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“…Concordantly, our study shows a marked increase of plasma apoA-V levels in HTG subjects. Importantly, the concept that apoA-V and TG are indeed positively related is supported by very recent findings by Dallinga-Thie et al (30), Vaessen et al (31), and Henneman et al (32) in patients with type II diabetes, apparently healthy individuals, and patients with severe HTG, respectively.…”

Section: Discussionmentioning

confidence: 77%

Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia

Schaap

Nierman

Berbée

et al. 2006

Journal of Lipid Research

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The relevance of apolipoprotein A-V (apoA-V) for human lipid homeostasis is underscored by genetic association studies and the identification of truncation-causing mutations in the APOA5 gene as a cause of type V hyperlipidemia, compatible with an LPL-activating role of apoA-V. An inverse correlation between plasma apoA-V and triglyceride (TG) levels has been surmised from animal data. Recent studies in human subjects using (semi)quantitative immunoassays, however, do not provide unambiguous support for such a relationship. Here, we used a novel, validated ELISA to measure plasma apoA-V levels in patients (n 5 28) with hypertriglyceridemia (HTG; 1.8-78.7 mmol TG/l) and normolipidemic controls (n 5 42). Unexpectedly, plasma apoA-V levels were markedly increased in the HTG subjects compared with controls (1,987 vs. 258 ng/ml; P , 0.001). In the HTG group, apoA-V and TG were positively correlated (r 5 10.44, P 5 0.02). In addition, we noted an increased level of the LPL-inhibitory protein apoC-III in the HTG group (45.8 vs. 10.6 mg/dl in controls; P , 0.001). The correlation between apoA-V and TG levels in the HTG group disappeared (partial r 5 10.09, P 5 0.65) when controlling for apoC-III levels. In contrast, apoC-III and TG remained positively correlated in this group when controlling for apoA-V (partial r 5 10.43, P 5 0.025). Our findings suggest that in HTG patients, increased TG levels are accompanied by high plasma levels of apoA-V and apoC-III, apolipoproteins with opposite modes of action. This study provides evidence for a complex interaction between apoA-V and apoC-III in patients with severe HTG. The recognition of hypertriglyceridemia (HTG) as an independent risk factor for cardiovascular pathologies (1) necessitates the identification of the factors involved in the regulation of plasma triglyceride (TG) levels. Along with esterified cholesterol, TGs constitute the neutral lipid core of chylomicrons, VLDL, and their remnants. LPL is the principal enzyme involved in the degradation of TG in plasma. The hydrolytic action of LPL requires the presence of a cofactor [i.e., apolipoprotein C-II (apoC-II)] and is modulated by a number of other factors (2-4). Important negative regulators are apoC-III and the recently identified angiopoietin-like proteins ANGPTL3 and ANGPTL4 (3,(5)(6)(7). In addition to these negative effectors, the novel apolipoprotein apoA-V was identified as a positive effector of LPL activity (8-10).ApoA-V has readily become recognized as an important determinant of plasma TG levels in humans and mice since its discovery 5 years ago (11,12). Animal experiments using different strategies of underexpression and overexpression indicated an inverse relationship between apoa5 gene expression and plasma TG (11, 13) [e.g., adenoviral expression of apoa5 in mice resulted in a dose-dependent reduction of plasma TG levels (9)]. In humans, genetic variation at the APOA5 locus has been associated with HTG (11,[14][15][16][17]. Moreover, homozygosity for truncation-causing mutations (Q148X and Q...

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Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

Cited by 79 publications

References 37 publications

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

Endocytosis of Apolipoprotein A-V by Members of the Low Density Lipoprotein Receptor and the Vps10p Domain Receptor Families

Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia

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