APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency

Calandra, Sebastiano; Oliva, Claudio Priore; Tarugi, Patrizia; Bertolini, S

doi:10.1097/01.mol.0000217892.00618.54

Cited by 88 publications

(58 citation statements)

References 46 publications

(54 reference statements)

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“…The physicochemical properties of APOA5 protein moiety, has lipid-binding activity as demonstrated by the ability to form lipid-protein complexes. Also, APOA5 displays high affinity, low elasticity and slow binding kinetics at hydrophobic interfaces and leads to the postulation that it might retard TG-rich particle assembly in the liver and inhibit the secretion of VLDL [25]. The other argument is that APOA5 is an activator of intravascular TG hydrolysis by LPL.…”

Section: Resultsmentioning

confidence: 99%

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

et al. 2008

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Previously we have shown that intestinal cells efficiently take up oxidized fatty acids (OxFAs) and that atherosclerosis is increased when animals are fed a high cholesterol diet in the presence of oxidized linoleic acid. Interestingly, we found that in the absence of dietary cholesterol, the oxidized fatty acid fed low-density lipoprotein (LDL) receptor negative mice appeared to have lower plasma triglyceride (TG) levels as compared to animals fed oleic acid. In the present study, we fed C57BL6 mice a normal mice diet supplemented with oleic acid or oxidized linoleic acid (at 18 mg/animal/ day) for 2 weeks. After the mice were sacrificed, we measured the plasma lipids and collected livers for the isolation of RNA. The results showed that while there were no significant changes in the levels of total cholesterol and high-density lipoprotein cholesterol (HDLc), there was a significant decrease (41.14%) in the levels of plasma TG in the mice that were fed oxidized fatty acids.The decreases in plasma TG levels were accompanied by significant increases (P < 0.001) in the expressions of APOA5 and acetyl-CoA oxidase genes as well as a significant (P < 0.04) decrease in APOClll gene expression. Oxidized lipids have been suggested to be ligands for peroxisome proliferator-activated receptor (PPARα). However, there were no increases in the mRNA or protein levels of PPARα in the oxidized linoleic acid fed animals. These results suggest that oxidized fatty acids may act through an APOA5/APOClll mechanism that contributes to lowering of TG levels other than PPARα induction.

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Section: Resultsmentioning

confidence: 99%

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

et al. 2008

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“…1,2 Transgenic mice overexpressing the apo A5 gene, APOA5, showed decreased plasma triglycerides whereas knock-out mice lacking the APOA5 gene showed several fold increase in plasma triglycerides. 3 The plasma level of apo A5 correlates positively with high-density lipoprotein (HDL) cholesterol, but negatively with triglycerides.…”

Section: Introductionmentioning

confidence: 99%

A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese

et al. 2010

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Single nucleotide polymorphisms (SNPs) in the apolipoprotein A5 (APOA5) gene have been associated with hypertriglyceridaemia. We investigated which SNPs in the APOA5 gene were associated with triglyceride levels in two independent Chinese populations. In all, 1375 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study were genotyped for five tagging SNPs chosen from HapMap. Replication was sought in 1996 subjects from the Guangzhou Biobank Cohort Study. Among the five SNPs, rs662799 (-1131T4C) was strongly related to log-transformed triglyceride levels among Hong Kong subjects (b¼0.192, P¼2.6Â10 À13 ). Plasma triglyceride level was 36.1% higher in CC compared to TT genotype. This association was confirmed in Guangzhou subjects (b¼0.159, P¼1.3Â10 À12 ), and was significantly irrespective of sex, age group, obesity, metabolic syndrome, hypertension, diabetes, smoking and alcohol drinking. The odds ratios and 95% confidence interval for plasma triglycerides Z1.7 mmol/l associated with TC and CC genotypes were, respectively, 1.81 (1.37-2.39) and 2.22 (1.44-3.43) in Hong Kong and 1.27 (1.05-1.54) and 1.97 (1.42-2.73) in Guangzhou. Haplotype analysis suggested the association was due to rs662799 only. The corroborative findings in two independent populations indicate that the APOA5-1131T4C polymorphism is an important and clinically relevant determinant of plasma triglyceride levels in the Chinese population.

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“…Genetic variation in the human APOA5 locus correlate with changes in plasma lipoprotein levels (2)(3)(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).…”

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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

104

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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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APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency

Cited by 88 publications

References 46 publications

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms

A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese

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

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