Familial combined hyperlipidaemia linked to the apolipoprotein AI–CIII–AIV gene cluster on chromosome 11q23q–q24

Wojciechowski, A.P.; Farrall, Martin; Cullen, Paul; Wilson, Teresa; Bayliss, Jayne; Farren, B; Griffn, Bruce A.; Caslake, Muriel; Packard, Christopher J.; Shepherd, James; Thakker, Rajesh; Scott, James

doi:10.1038/349161a0

Cited by 174 publications

(110 citation statements)

References 19 publications

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“…Both fibratesFagonists of peroxisome proliferator-activated receptor alpha (PPARa)Fand retinoidsFpanagonists of the retinoic acid receptors RAR and RXRFwere commonly shown to influence triglyceridemia through changing the expression of apolipoprotein C-III (ApoC-III) gene. 6,7 This gene alone as well as the whole ApoA-I/C-III/A-IV cluster (and most recently its new member, ApoA-V) were associated with dyslipidemia in human populations and animal models 3,8 and were also suggested as putative candidates for hypertriglyceridemia in a genetic model of insulin resistance syndrome, polydactylous (PD/Cub) rat strain [9][10][11][12][13][14] (http:// www.img.cas.cz/fb/, Table 1). Therefore, we examined the effect of fenofibrate and isotretinoin administration on metabolic profile, insulin sensitivity and lipolysis in tissues and the expression of ApoC-III and one of its proposed upstream regulatory genes, hepatocyte nuclear factor-4 (Hnf-4), in the PD/Cub rat strain.…”

Section: Introductionmentioning

confidence: 99%

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

et al. 2004

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OBJECTIVE:To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolismForal glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/ glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoidinduced hypertriglyceridemia.

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Section: Introductionmentioning

confidence: 99%

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

et al. 2004

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“…More specifically, the APOA1/C3/A4 apolipoprotein gene cluster is tightly linked to plasma lipid profiles. Indeed, mutations in members of this cluster have been shown to cause severe dyslipidemia and heightened atherosclerosis susceptibility (5)(6)(7)(8). A comparative genomic characterization of the APOA1/C3/A4 gene cluster flanking regions led to the recent identification of a new apolipoprotein gene, apolipoprotein A5 (APOA5), present in both mice and humans (9).…”

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Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators

Vu‐Dac

Gervois

Jakel

et al. 2003

Journal of Biological Chemistry

194

138

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The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor ␣ target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.Coronary heart disease continues to be a major cause of morbidity and mortality worldwide. Several epidemiological studies established that, in addition to elevated low density lipoprotein and reduced high density lipoprotein level, elevated triglycerides (TGs) 1 constitute an independent risk factor for coronary heart disease (1, 2). In addition, hypertriglyceridemia is often associated with the metabolic syndrome that characterizes diabetes and obesity (3, 4). Therefore, the identification of factors or genes affecting triglyceride metabolism is of significant medical importance for the correction of hypertriglyceridemia and associated coronary heart disease.Apolipoproteins play a determinant role in lipoprotein metabolism and in lipid homeostasis. More specifically, the APOA1/C3/A4 apolipoprotein gene cluster is tightly linked to plasma lipid profiles. Indeed, mutations in members of this cluster have been shown to cause severe dyslipidemia and heightened atherosclerosis susceptibility (5-8). A comparative genomic characterization of the APOA1/C3/A4 gene cluster flanking regions led to the recent identification of a new apolipoprotein gene, apolipoprotein A5 (APOA5), present in both mice and humans (9). apoAV shares homology with several apolipoproteins, most prominently apoAIV, and is 368 and 366 amino acids long in mice and human, respectively. This gene appears to be predominantly expressed in the liver and resides on high density lipoprotein and very low density lipoprotein particles (9, 10).The properties of apoAV were investigated by creating human APOA5 transgenic and knock-out mice and by searching for associations between human APOA5 polymorphisms and plasma lipid parameters. The Apoa5 knock-out mice display a 400% increase in plasma triglycerides compared with wild-type mice, while APOA5 transgenics exhibit triglyceride levels corresponding to one-third of those in control mice. This determinant link between APOA5 and triglycerides was supported in several separate human studies through the consistent demonstration of associations betwe...

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“…14 Finally, genetic studies have supported that common polymorphisms in APOC3 are also associated with triglyceride levels in humans. [15][16][17][18][19][20] The inverse effect of APOA5 and APOC3 on plasma triglycerides in vivo raises the question whether they mediate their effect through either a shared or an independent mechanism. One hypothesis is that alteration in APOA5 or APOC3 levels in transgenic or knockout mice simply disrupts the plasma protein level of the other apolipoprotein and accounts for the abnormal triglyceride phenotype.…”

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confidence: 99%

Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice

Baroukh

Baugé

Akiyama

et al. 2004

ATVB

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Objective-Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides. Methods and Results-To address this issue, we generated independent lines of mice that either overexpressed ("double transgenic") or completely lacked ("double knockout") both apolipoprotein genes. We report that both "double transgenic" and "double knockout" mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the "double transgenic" mice are Ϸ500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration. Conclusions-Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner. Key Words: apolipoprotein Ⅲ triglyceride Ⅲ transgenic mice A polipoproteins constitute a class of polypeptides found on plasma lipoprotein particles that play an important role in lipid transport and metabolism. Alterations in the level or structure of these molecules have been shown to dramatically impact plasma lipid concentrations and, in many cases, atherosclerosis susceptibility in humans as well as in mice. In mammals, evidence exists that some of the apolipoprotein family members are evolutionarily related as the result of gene duplication events. For instance, apolipoprotein AI, AIV, and E all share amino acid identity and similarity, supportive of a common ancestral origin. 1 We recently identified an additional member of this apolipoprotein family, named ApoAV, through the use of human-mouse genomic sequence comparisons. 2 APOA5 is located within the welldescribed APOA1/A4/C3 gene cluster on human chromosome 11q23. 3 Although APOA5 is most closely related to APOA4, manipulations of APOA5 levels in mice resulted in profound effects on plasma triglyceride concentrations, a phenotype not present in APOA4 mouse models. 2,4,5 APOA5 transgenic mice displayed significantly reduced (Ϫ70%) triglyceride concentrations whereas apoA5 knockouts had an increase (ϩ400%) in this lipid parameter. 2 Further genetic studies in humans have consistently reported strong association between common APOA5 polymorphisms and plasma triglyceride concentrations. 2,6 -11 In addition to APOA5, the neighboring APOC3 gene has also been reported to have a striking effect on human and mouse plasma triglyceride concentrations. However, APOC3 has an opposite impact on triglycerides, with transgenic mice having increased concentrations (ϩ200% to 2000%) and knocko...

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Familial combined hyperlipidaemia linked to the apolipoprotein AI–CIII–AIV gene cluster on chromosome 11q23q–q24

Cited by 174 publications

References 19 publications

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators

Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice

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