Characterization of apolipoprotein A-V structure and mode of plasma triacylglycerol regulation

Wong, Kasuen; Ryan, Robert O.

doi:10.1097/mol.0b013e328133856c

Cited by 43 publications

(37 citation statements)

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“…APOA5 interaction with heparan sulfate proteoglycans (HSPGs) is shown to facilitate apoC-II activation of lipoprotein lipase (LPL), resulting in accelerated triacylglycerol hydrolysis [33]. The APOA5 T-1131C and G553T otype as shown in Table 2, which seems to be explained by the reduction in serum TG levels observed in Table 4.…”

Section: Discussionmentioning

confidence: 61%

Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese — a cross-sectional data from the J-MICC Study

et al. 2012

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IN THE rEcENT dEcadEs, sedentary lifestyles became more and more common, and lifestyle-related Associations of apolipoprotein A5 (APOA5), glucokinase (GCK)and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese -a cross-sectional data from the J-MICC Study 770-8503, Japan 11) Center for Genomic Medicine, RIKEN, Yokohama 230-0045, Japanabstract. This study examined the associations of the APOA5 T-1131C (rs662799), G553T (Cys185Gly, rs2075291), GCK G-30A (rs1799884), GCKR A/G at intron 16 (rs780094) and T1403C (Leu446Pro, rs1260326) polymorphisms with serum lipid and glucose levels in Japanese, considering lifestyle factors. Study subjects were 2,191 participants (aged 35-69 years, 1,159 males) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Dyslipidemia was defined as fasting serum triglycerides (FTG) ≥ 150 mg/dL and/or HDL-cholesterol (HDL-C) < 40 mg/dL, while dysglycemia was as fasting blood sugar (FBS) ≥ 110 mg/dL. When those with APOA5 -1131 T/T or 553 G/G were defined as references, those with APOA5 -1131 T/C, C/C or 553 G/T, T/T demonstrated significantly elevated risk of dyslipidemia (age-and sex-adjusted odds ratio: 1.77 [95% confidence interval:1.39-2.27], 3.35 [2.41-4.65], 2.23 [1.64-3.02] and 13.78 [3.44-55.18], respectively). Evaluation of FTG, HDL-C or FBS levels according to the genotype revealed that FTG and HDL-C levels were significantly associated with the APOA5 T-1131C and G553T polymorphisms, FTG with the GCKR rs780094 and rs1260326 polymorphisms, and FBS with the GCKR rs780094 and rs1260326 polymorphisms. Moreover, a significant positive interaction between APOA5 553 G/T+T/T genotypes and fat intake ≥ 25% of total energy for the risk of dyslipidemia was observed. Our crosssectional study confirmed the essential roles of the polymorphisms of the APOA5, GCK and GCKR in the lipid or glucose metabolism disorders, and suggested the importance of fat intake control in the individualized prevention of dyslipidemia.

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Section: Discussionmentioning

confidence: 61%

Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese — a cross-sectional data from the J-MICC Study

et al. 2012

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“…ApoA-V may regulate triglyceride metabolism, including VLDL assembly, LPL activity, and VLDL receptor binding ( 35 ). However, the association between apoA-V and plasma triglycerides remains unclear (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Ooi

Chan

Watts

et al. 2011

Journal of Lipid Research

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Supplementary key words kinetics • lipoprotein metabolism • triglyceridesCardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) ( 1 ). While the precise mechanisms for increased CVD risk are unknown, both traditional and novel CVD risk factors have been implicated ( 1, 2 ). Dyslipidemia, a well-established risk factor for CVD in the general population, is highly prevalent in CKD ( 3, 4 ). The most frequent dyslipoproteinemic phenotype patterns are elevated plasma concentrations of triglycerides and increased numbers of atherogenic triglyceride-rich lipoprotein (TRL) particles, particularly VLDL and intermediate-density lipoprotein (IDL) ( 3, 4 ). The regulation of TRL metabolism in CKD, however, is poorly understood.Apolipoprotein C-III (apoC-III) is an 8.8 kDa glycoprotein synthesized by the liver and intestines ( 5 ). ApoC-III is highly associated with hypertriglyceridemia and is a powerful independent predictor of CVD risk in subjects without renal disease ( 5 ). In the circulation, apoC-III is associated with TRL and HDL exchanging rapidly between these lipoproteins ( 6 ). In vitro studies demonstrate that apoC-III Abstract Moderate chronic kidney disease (CKD) (defi ned by an estimated glomerular fi ltration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age-and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2 H 3 ]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III ( P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was signifi cantly and negatively correlated with apoC-III FCR ( r = ؊ 0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR ( P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR ( P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modifi cation of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate

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“…Apolipoprotein A-V (apoA-V), first described in 2001 (1,2), has emerged as an important modulator of triglyceride (TG) metabolism (3). The protein is synthesized solely by the liver and is found in plasma associated with HDL and VLDL.…”

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confidence: 99%

Intracellular lipid droplet targeting by apolipoprotein A-V requires the carboxyl-terminal segment

Shu¹,

Ryan

Forte³

2008

Journal of Lipid Research

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The expression of apolipoprotein A-V (apoA-V) in hepatoma cells results in homing of this protein to intracellular lipid droplets. When hepatoma cells transfected with a full-length apoA-V-green fluorescent protein fusion protein were cultured in medium that was not supplemented with oleic acid (OA), intracellular lipid droplet size and number were reduced compared with those of cells supplemented with OA. Confocal microscopy studies revealed that apoA-V associates with lipid droplets under both conditions. To define the structural requirements for apoA-V lipid droplet association, hepatoma cells were transfected with a series of C-terminal truncated apoA-V variants. Confocal microscopy analysis revealed that, in a manner similar to mature full-length apoA-V (343 amino acids), truncation variants apoA-V(1-292), apoA-V(1-237), and apoA-V(1-191) associated with lipid droplets, while apoA-V(1-146) did not. Western blot analysis of the relative abundance of apoA-V in cell lysates versus conditioned medium indicated that apoA-V variants associated with lipid droplets were poorly secreted while apoA-V(1-146) was efficiently secreted. Ultracentrifugation of conditioned medium revealed that, unlike full-length apoA-V, which associates with lipoproteins, apoA-V(1-146) was present solely in the lipoprotein-deficient fraction. Deletion of the N-terminal signal peptide from apoA-V resulted in an inability of the protein to be secreted into the medium, although it associated with lipid droplets. Taken together, these data suggest that the C terminus of apoA-V is essential for lipid droplet association in transfected hepatoma cells and lipoprotein association in conditioned medium while the signal peptide is required for extracellular trafficking of this protein. (1, 2), has emerged as an important modulator of triglyceride (TG) metabolism (3). The protein is synthesized solely by the liver and is found in plasma associated with HDL and VLDL. Newly synthesized apoA-V consists of 366 amino acids, where the first 23 residues form the cleavable signal peptide. The mature, secreted form of apoA-V consists of 343 residues (39 kDa). The protein is extremely hydrophobic and not readily soluble in aqueous medium; however, once bound to lipid, it is soluble and stable (4). We recently reported that apoA-V, overexpressed in hepatoma cell lines, associates with cytoplasmic lipid droplets despite being synthesized with a signal peptide (5). Although the protein was poorly secreted from hepatoma cells, it was found in association with lipoproteins in conditioned medium. In hepatocytes, lipid droplets are a storage form of neutral lipids (particularly TG) that may be used for production of VLDL. Since it is conceivable that apoA-V lipid droplet association may be relevant to plasma TG homeostasis, we explored these observations further to determine structural elements within apoA-V that are involved in lipid droplet association and apoA-V secretion.It was previously proposed that the C-terminal segment of apoA-V is required for li...

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Characterization of apolipoprotein A-V structure and mode of plasma triacylglycerol regulation

Cited by 43 publications

References 38 publications

Associations of <i>apolipoprotein A5 (APOA5), glucokinase (GCK)</i> and <i>glucokinase regulatory protein (GCKR)</i> polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese — a cross-sectional data from the J-MICC Study

Associations of <i>apolipoprotein A5 (APOA5), glucokinase (GCK)</i> and <i>glucokinase regulatory protein (GCKR)</i> polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese — a cross-sectional data from the J-MICC Study

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Intracellular lipid droplet targeting by apolipoprotein A-V requires the carboxyl-terminal segment

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