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Len A. Pennacchio - One of the best experts on this subject based on the ideXlab platform.

  • Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol
    2020
    Co-Authors: Itamar Grosskopf, Len A. Pennacchio, Edward M. Rubin, Nadine Baroukh, Sung-joon Lee, Yehuda Kamari, Dror Harats, Allen D Cooper
    Abstract:

    Objective-ApoAV, a newly discovered apoprotein, affects plasma triglyceride level. To determine how this occurs, we studied triglyceride-rich lipoprotein (TRL) metabolism in mice deficient in apoAV. Methods and Results-No significant difference in triglyceride production rate was found between APOA5 Ϫ/Ϫ mice and controls. The presence or absence of apoAV affected TRL catabolism. After the injection of 14 C-palmitate and 3 H-cholesterol labeled chylomicrons and 125 I-labeled chylomicron remnants, the disappearance of 14 C, 3 H, and 125 I was significantly slower in APOA5 Ϫ/Ϫ mice relative to controls. This was because of diminished lipolysis of TRL and the reduced rate of uptake of their remnants in APOA5 Ϫ/Ϫ mice. Observed elevated cholesterol level was caused by increased high-density lipoprotein (HDL) cholesterol in APOA5 Ϫ/Ϫ mice. VLDL from APOA5 Ϫ/Ϫ mice were poor substrate for lipoprotein lipase, and did not bind to the low-density lipoprotein (LDL) receptor as well as normal very-low-density lipoprotein (VLDL). LDL receptor levels were slightly elevated in APOA5 Ϫ/Ϫ mice consistent with lower remnant uptake rates. These alterations may be the result of the lower apoE-to-apoC ratio found in VLDL isolated from APOA5 Ϫ/Ϫ mice. T he level of triglycerides in the blood has been correlated with the risk of atherosclerosis in a variety of studies. 1,2 Apoproteins of triglyceride-rich lipoproteins (TRL) play an important role in triglyceride transport. In particular, ApoCs and apoE 3,4 strongly affect TRL metabolism and thus plasma triglyceride levels. ApoAV is a newly discovered apolipoprotein, which was identified independently by 2 groups. Conclusions-These ApoAV could influence triglyceride levels through alterations in the hepatic triglyceride secretion rate, or alternatively in the rate of catabolism of triglycerides within plasma. We report that the presence or absence of apoAV does not affect triglyceride production. The absence of apoAV leads to a reduction in the rate of removal of triglycerides with the accumulation of larger than normal very-low-density lipoprotein (VLDL) particles in the plasma. These particles are paradoxically worse substrates for lipoprotein lipase than Origina

  • in vivo characterization of human APOA5 haplotypes
    Genomics, 2007
    Co-Authors: Nadav Ahituv, Len A. Pennacchio, Jean-charles Fruchart, Jennifer A Akiyama, Audrey Chapmanhelleboid
    Abstract:

    Increased plasma triglyceride concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effects of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy APOA5 haplotypes at a targeted location (Hprt) in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 or minor APOA5*2 haplotype, the introduction of the single APOA5*3-defining allele (19W) resulted in three fold lower ApoAV plasma levels, consistent with existing genetic association studies. These results indicate that the S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides, supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

  • apolipoprotein av accelerates plasma hydrolysis of triglyceride rich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
    Journal of Biological Chemistry, 2005
    Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg Heeren
    Abstract:

    Abstract Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the APOA5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of APOA5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.

  • apolipoprotein av accelerates plasma hydrolysis of triglyceriderich lipoproteins by interaction with proteoglycan bound lipoprotein lipase
    Journal of Biological Chemistry, 2005
    Co-Authors: Martin Merkel, Len A. Pennacchio, B Loeffler, Malte Kluger, Nathalie Fabig, Gesa Geppert, A Laatsch, Joerg Heeren
    Abstract:

    Apolipoprotein A5 (APOA5) is associated with differences in triglyceride levels and familial combined hyperlipidemia. In genetically engineered mice, apoAV plasma levels are inversely correlated with plasma triglycerides. To elucidate the mechanism by which apoAV influences plasma triglycerides, metabolic studies and in vitro assays resembling physiological conditions were performed. In human APOA5 transgenic mice (hAPOA5tr), catabolism of chylomicrons and very low density lipoprotein (VLDL) was accelerated due to a faster plasma hydrolysis of triglycerides by lipoprotein lipase (LPL). Hepatic VLDL and intestinal chylomicron production were not affected. The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the APOA5 knock-out and the hAPOA5tr to an lpl-deficient background. Increased LPL activity completely normalized hypertriglyceridemia of APOA5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced. To reflect the physiological situation in which LPL is bound to cell surface proteoglycans, we examined hydrolysis in the presence or absence of proteoglycans. Without proteoglycans, apoAV derived either from triglyceride-rich lipoproteins, hAPOA5tr high density lipoprotein, or a recombinant source did not alter the LPL hydrolysis rate. In the presence of proteoglycans, however, apoAV led to a significant and dose-dependent increase in LPL-mediated hydrolysis of VLDL triglycerides. These results were confirmed in cell culture using a proteoglycan-deficient cell line. A direct interaction between LPL and apoAV was found by ligand blotting. It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis.

  • insulin mediated down regulation of apolipoprotein a5 gene expression through the phosphatidylinositol 3 kinase pathway role of upstream stimulatory factor
    Molecular and Cellular Biology, 2005
    Co-Authors: Maxime Nowak, Len A. Pennacchio, Edward M. Rubin, Geneviève Martin, Bart Staels, Heidelinde Jakel, Audrey Helleboidchapman, Marja-riitta Taskinen, Daniel Duransandoval, Jamila Fruchartnajib
    Abstract:

    The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.

Ruixing Yin - One of the best experts on this subject based on the ideXlab platform.

  • interactions between the apolipoprotein a1 c3 a5 haplotypes and alcohol consumption on serum lipid levels
    Alcoholism: Clinical and Experimental Research, 2013
    Co-Authors: Ruixing Yin, Shangling Pan, Chengwu Liu, Weixiong Lin, Dezhai Yang
    Abstract:

    Background The interactions between apolipoprotein (Apo) A1/C3/A5 haplotypes and alcohol consumption on serum lipid profiles have not been previously explored. The present study was undertaken to detect the polymorphisms of ApoA1 −75 bp G>A (rs1799837), ApoC3 3238C>G (rs5128), APOA5 −1131T>C (rs662799), APOA5 c.553G>T (rs2075291), and APOA5 c.457G>A (rs3135507) and the interactions between their haplotypes and alcohol consumption on serum lipid levels. Methods Genotyping was performed in 1,030 unrelated subjects (516 nondrinkers and 514 drinkers) aged 15 to 89. The interactions between ApoA1/C3/A5 haplotypes and alcohol consumption on serum lipid levels were detected by factorial regression analysis after controlling for potential confounders. Results The frequencies of ApoC3 3238 CG/GG genotypes and ApoA1 −75 bp A allele in nondrinkers were higher in females than in males (p  1% in our study population. The haplotypes of G–G–T–C–G (in the order of c.553G>T, c.457G>A, −1131T>C, 3238C>G, and −75 bp G>A), G–G–T–C–A, and G–G–C–G–G were shown consistent interactions with alcohol consumption to increase serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), and ApoA1 levels (p < 0.05 to 0.001). The interactions between G–G–T–G–G (HDL-C and ApoA1), G–G–C–C–A (ApoA1), G–A–T–C–G (triglyceride), G–G–T–C–G (ApoA1/ApoB ratio), and G–G–C–G–G (ApoB) haplotypes and alcohol consumption on serum lipid levels were also detected (p < 0.05 to 0.001); the levels of these serum lipid parameters were significantly higher in drinkers than in nondrinkers. Conclusions The differences in serum lipid parameters between drinkers and nondrinkers might partly result from different interactions between the ApoA1/C3/A5 haplotypes and alcohol consumption.

  • apolipoprotein a1 c3 a5 haplotypes and serum lipid levels
    Heart, 2011
    Co-Authors: Ruixing Yin, Chaoqiang Lai
    Abstract:

    Background and aims Single nucleotide polymorphisms (SNPs) at the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster have been examined in relation to lipid metabolism and cardiovascular disease risk. However, the previous findings are inconsistent. The present study was undertaken to detect the association between ApoA1/C3/A5 haplotypes and serum lipid levels in the general Chinese population. Methods A total of 1030 unrelated subjects (492 males and 538 females) aged 15–89 were randomly selected from our previous samples. Genotyping of the ApoA1 –75bp G>A, ApoC3 3238C>G, APOA5 –1131T>C, APOA5 c.553G>T and APOA5 c.457G>A was performed by PCR and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Pair-wise linkage disequilibria (LD) and haplotype analysis among the five SNPs were estimated. Results The levels of high-density lipoprotein cholesterol (HDL-C) and ApoA1 were lower in males than in females (P A was in LD with the other four SNPs; ApoC3 3238C>G was in LD with APOA5 –1131T>C; APOA5 –1131T>C was in LD with c.553G>T and c.457G>A. There was no significant difference in the allelic and genotypic frequencies of the all SNPs except ApoC3 3238C>G between males and females. The levels of triglyceride (TG) in males and HDL-C and the ratio of ApoA1 to ApoB in females were different among the three genotypes of the ApoA1 –75bp G>A (P G (P C (P T (P A (P 1% identified in the cluster in our population. At the global level, the haplotypes comprised of all five SNPs were significantly associated with all seven lipid traits. In particular, haplotype G-A-T-C-G (6%) and G-A-T-C-G (4%) showed consistent association with LDL-C, TC, ApoA1, ApoB and the ratio of ApoA1 to ApoB. In addition, carriers of haplotype G-G-T-C-G (26%) had increased serum concentration of HDL-C and ApoA1, whereas carriers of G-G-C-G-G (15%) had high concentrations of TG, TC and ApoB. The authors also found that haplotypes with five SNPs explain much more serum lipid variation than any single SNP alone, especially for TG (4.4% for haplotype vs 2.4% for –1131T>C max based on R-square) and HDL-C (5.1% for haplotype vs 0.9% for c.553G>T based on R-square). Serum lipid parameters were also correlated with genotypes and several environment factors such as gender, age, weight, body mass index, alcohol consumption, cigarette smoking and blood pressure in the population. Conclusions Several common SNPs and their haplotypes at the ApoA1/C3/A5 gene cluster are closely associated with modifications of serum lipid parameters in the general Chinese population.

  • interactions of the apolipoprotein a5 gene polymorphisms and alcohol consumption on serum lipid levels
    PLOS ONE, 2011
    Co-Authors: Ruixing Yin, Wanying Liu, Lin Zhang
    Abstract:

    Background Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of APOA5–1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels. Methodology/Principal Findings A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P C genotypes and alcohol consumption on ApoB levels (P T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P A genotypes and alcohol consumption on TG levels (P C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05–0.01). Conclusions The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the APOA5 gene polymorphisms and alcohol consumption.

David G Hunter - One of the best experts on this subject based on the ideXlab platform.

  • associations of the apolipoprotein a1 c3 a4 a5 gene cluster with triglyceride and hdl cholesterol levels in women with type 2 diabetes
    Atherosclerosis, 2007
    Co-Authors: Simin Liu, Nader Rifai, David G Hunter
    Abstract:

    Abstract The apolipoprotein gene cluster (APOA1/C3/A4/A5) was recently associated with triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) in non-diabetic population. Little is known whether the variations in these genes affect lipid homeostasis in patients with type 2 diabetes. We examined the associations of 10 polymorphisms at APOA1/C3/A4/A5 gene cluster with blood lipids among 902 diabetic women. A linkage disequilibrium (LD) breakdown was observed between APOA5 and other genes. APOA5 S19W was associated with significantly higher fasting TG levels ( P =0.001). Two common haplotypes encompassing four APOA5 polymorphisms (SNP1, SNP2, S19W, and SNP3) were associated with 35.6mg/dL (haplotype 2212, APOA5*2, P =0.016) and 57.8mg/dL (haplotype 1121, APOA5*3, P =0.0002) higher fasting TG levels compared with the most common (haplotype 1111, APOA5*1), respectively. Adjustment for age, BMI, and other covariates did not appreciably change such associations. In addition, APOC3 promoter polymorphism −455T/C showed significant associations with fasting TG levels ( P =0.006), whereas APOA4 +347T/A showed significant associations with lower levels of HDL-C ( P =0.017). Our results indicate that the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes.

Philippa J Talmud - One of the best experts on this subject based on the ideXlab platform.

  • APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis
    Atherosclerosis, 2015
    Co-Authors: Montse Guardiola, Philippa J Talmud, L Masana, Montserrat Cofan, Isabel De Castrooros, Ana Cenarro, Nuria Plana, Emilio Ros, Fernando Civeira, J Ribalta
    Abstract:

    Abstract Background Triglycerides (TG) are the initiators of the metabolic changes leading to the atherogenic dyslipidemia, which is a major inducer of atherosclerosis as a result of quantitative and qualitative changes in lipoprotein subclass distributions. We hypothesized that variation at the of APOA5 gene locus, encoding apoAV, a key regulator of TG levels, significantly affect lipoprotein subclass distributions toward a more atherogenic pattern in both hyperTG patients and dyslipemic patients. Methods We recruited four hundred and twenty-two subjects attending a Lipid Clinic, prior to lipid-lowering treatment. We genotyped two APOA5 variants, rs662799 (-1131T>C) and rs3135506 (S19W). Circulating lipoproteins were determined by nuclear magnetic resonance (NMR). Intima-media thickness (IMT) was evaluated using B-mode ultrasound. Results Carriers of the rare alleles of rs662799 and rs3135506 compared to common allele homozygotes, had a significantly proatherogenic profile of the VLDL and LDL subclasses, resulting in increased concentrations of the proatherogenic subclasses, large VLDLs (+133%, p  The observed effects were significantly stronger in patients with a BMI ≥ 25 kg/m 2 and in male and female patients with a waist circumference ≥90 cm or ≥85 cm, respectively. Conclusion In a dyslipemic population, genetic variants of APOA5 modulate lipoprotein subclass distributions, inducing an atherogenic profile associated with IMT defined subclinical atherosclerosis.

  • the functional interaction on in vitro gene expression of APOA5 snps defining haplotype APOA5 2 and their paradoxical association with plasma triglyceride but not plasma apoav levels
    Biochimica et Biophysica Acta, 2008
    Co-Authors: Jutta Palmen, Steve E Humphries, Andrew J Smith, Birgit Dorfmeister, Wendy Putt, Philippa J Talmud
    Abstract:

    Plasma triglyceride (TG) and apoAV levels are reported to be positively correlated, yet SNPs defining haplotype APOA52 have consistently shown association with elevated plasma triglyceride (TG) but not plasma apoAV levels. We previously reported that individually -1131T>C, -3A>G and +1891T>C did not influence luciferase activity or in vitro translation efficiency. To investigate the combined effect of these SNPs additional constructs were examined. Compared to the wildtype -1131T/-3A/+1891T (TAT), the triple rare allele construct -1131C/-3G/+1891C (CGC) conferred 46% lower luciferase activity (p G in the Kozak sequence as functional, affecting translation initiation and driving the haplotype effects, while showing interaction with +1891T>C and to a lesser extent -1131T>C. A paradox arises since these results predict that APOA52 will lead to reduced apoAV with concomitant reduced LPL activation or lipoprotein-receptor interaction, resulting in higher plasma TG levels. We conclude that APOA5 expression, and not circulating plasma apoAV levels, is causatively associated with plasma TG levels.

  • rare APOA5 mutations clinical consequences metabolic and functional effects an enid review
    Atherosclerosis, 2007
    Co-Authors: Philippa J Talmud
    Abstract:

    In 2001, a gene encoding a novel apolipoprotein (apo), APOA5, was identified by comparative human/mouse sequencing. The encoded protein, apoAV, had been missed in routine apolipoprotein identification because it occurs at very low plasma concentrations and only DNA analysis led to its identification. Knockout and transgenic mouse models of apoAV showed an inverse relationship with plasma triglyceride levels. In human studies, common APOA5 variants have shown near consistent association with elevated plasma TG levels, confirming apoAV as playing a role in human triglyceride metabolism. Based on mouse knockout models it was predicted that individuals with rare mutations in APOA5 would present with severe hypertriglyceridaemia and apoAV deficiency. However, considering the small number of mutation carriers identified to date, the mode of inheritance is variable and in the recessive form TG levels are within the normal range, and apoAV deficiency only occurs in the homozygous state. Furthermore, penetrance of the mutations is low and appears to require co-inheritance of a common APOA5 TG-raising allele as well as environmental factors for expression of the hypertriglyceridaemia. In this review the clinical and metabolic consequences and phenotype of the three APOA5 mutations reported to date, which lead to premature truncations of apoAV are described. The insight these truncated protein give to the structure-function relationship of apoAV is explored and the relative importance of plasma and liver apoAV discussed.

  • determination of the functionality of common APOA5 polymorphisms
    Journal of Biological Chemistry, 2005
    Co-Authors: Philippa J Talmud, Jutta Palmen, Wendy Putt, Laurence Lins, Steve E Humphries
    Abstract:

    Common variants of APOA5 have consistently shown association with differences in plasma triglyceride (TG) levels. These single nucleotide polymorphisms (SNPs) fall into three common haplotypes: APOA5*1, with common alleles at all sites; APOA5*2, with rare alleles of –1131T→ C, –3A→ G, 751G→ T, and 1891T→ C; and APOA5*3, distinguished by the c56C→ G (S19W). Molecular modeling of the apoAV signal peptide (SP) showed an increased angle of insertion (65°) at the lipid/water interface of Trp-19 SP compared with Ser-19 SP (40°), predicting reduced translocation. This was confirmed by 50% reduction of Trp-19-encoded SP·secretory alkaline phosphatase (SEAP) fusion protein secreted into the medium from HepG2 cells compared with the Ser-19·SEAP fusion protein (p

  • APOA5 gene variants lipoprotein particle distribution and progression of coronary heart disease results from the locat study
    Journal of Lipid Research, 2004
    Co-Authors: Philippa J Talmud, Marja-riitta Taskinen, Steve Martin, Steve E Humphries, Heikki M Frick, Markku S Nieminen, Antero Y Kesaniemi, Amos Pasternack, Mikko Syvanne
    Abstract:

    Animal and human studies support a role for apolipoprotein A-V (apoA-V) in triglyceride (TG) metabolism. We examined the relationship of APOA5 −1131T>C and S19W with lipid subfractions and progression of atherosclerosis in the Lopid Coronary Angiography Trial. Compared with −1131TT men (n = 242), carriers of the −1131C allele (n = 54) had significantly higher total TG (P = 0.03), reflected in significantly increased VLDL mass [higher VLDL-TG, VLDL-cholesterol, VLDL-protein, and surface lipids (all P These results shed new light on the role of APOA5 variants in TG metabolism and coronary heart disease risk.

Jean-charles Fruchart - One of the best experts on this subject based on the ideXlab platform.

  • atheroprotective effect of human apolipoprotein a5 in a mouse model of mixed dyslipidemia
    Circulation Research, 2008
    Co-Authors: Roxane Mansouri, Bart Staels, Jamila Fruchartnajib, Philippe Gervois, E Bauge, Catherine Fievet, Jean-charles Fruchart
    Abstract:

    Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)APOA5 on atherogenesis. The influence of hAPOA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia. Our results demonstrate that hAPOA5 lowers plasma triglyceride levels in Western diet–fed ApoE2 knock-in mice. Moreover, atherosclerotic lesion development was significantly decreased in the hAPOA5 transgenic mice. Finally, pharmacologic activation of hAPOA5 expression by the peroxisome proliferator-activated receptor-α agonist fenofibrate resulted in an enhanced atheroprotection. These results identify an atheroprotective role of hAPOA5 in a mouse model of mixed dyslipidemia.

  • in vivo characterization of human APOA5 haplotypes
    Genomics, 2007
    Co-Authors: Nadav Ahituv, Len A. Pennacchio, Jean-charles Fruchart, Jennifer A Akiyama, Audrey Chapmanhelleboid
    Abstract:

    Increased plasma triglyceride concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effects of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy APOA5 haplotypes at a targeted location (Hprt) in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 or minor APOA5*2 haplotype, the introduction of the single APOA5*3-defining allele (19W) resulted in three fold lower ApoAV plasma levels, consistent with existing genetic association studies. These results indicate that the S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides, supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

  • is apolipoprotein a5 a novel regulator of triglyceride rich lipoproteins
    Annals of Medicine, 2006
    Co-Authors: Heidelinde Jakel, Maxime Nowak, Audrey Helleboidchapman, Jamila Fruchartnajib, Jean-charles Fruchart
    Abstract:

    Hypertriglyceridemia is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOA1/C3/A4 gene cluster. Data from mice over‐expressing or lacking APOA5 provide direct evidence that this apolipoprotein plays a role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARα, RORα, LXR and SREBP‐1c and this supports its function. Insulin and interleukins regulate APOA5 gene expression and provide novel clues for the role of this apolipoprotein. To date, the triglyceride lowering action of apoA‐V is attributed to the activation of lipoprotein lipase and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also ...

  • the liver x receptor ligand t0901317 down regulates APOA5 gene expression through activation of srebp 1c
    Journal of Biological Chemistry, 2004
    Co-Authors: Heidelinde Jakel, Len A. Pennacchio, Maxime Nowak, Jamila Fruchartnajib, Helene Dehondt, Emanuelle Moitrot, Dean W Hum, Jean-charles Fruchart
    Abstract:

    Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the liver X receptor (LXR) ligand-mediated effect on plasma triglyceride levels. Following treatment with the LXR ligand T0901317, we found that APOA5 mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 1c). In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5 promoter activity in a dose-dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements that were able to bind specifically SREBP-1c in gel-shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through small interfering RNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease of APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.

  • mechanism of triglyceride lowering in mice expressing human apolipoprotein a5
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Jamila Fruchartnajib, Len A. Pennacchio, E Bauge, Loredanstefan Niculescu, Tatiana Pham, Benoit Thomas, Corinne Rommens, Zouher Majd, Bryan H Brewer, Jean-charles Fruchart
    Abstract:

    Recently, we reported that apoAV plays key role in triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limit the elevation of triglycerides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.