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

Baroukh, Nadine; Baugé, Eric; Akiyama, Jennifer A.; Chang, Jessie; Afzal, Veena; Fruchart, Jean‐Charles; Rubin, Edward M.; Fruchart‐Najib, Jamila; Pennacchio, Len A.

doi:10.1161/01.atv.0000130463.68272.1d

Cited by 74 publications

(71 citation statements)

References 27 publications

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“…In our intact apoAI gene cluster transgenic lines, plasma triglyceride level increased ϳ3-fold compared with control mice. This value is higher than that from the apoAI/CIII/AIV/AV transgenic mouse generated by Baroukh et al (21) but is less than that in single human apoCIII transgenic mice (5-20-fold) (6) and in the 33-kb human apoAI/CIII/ AIV transgenic mice (4 -10-fold) (20). In addition, in our mutant transgenic mouse, deletion of the apoCIII enhancer did not affect human apoAV expression but significantly reduced human apoCIII expression, thus leading to a lower triglyceride level compared with control mice (Table I).…”

Section: Discussioncontrasting

confidence: 57%

“…This model carried only a relatively short genomic fragment and did not contain the newly identified apoAV. Because apoCIII and apoAV have predominant but opposite roles in triglyceride homeostasis, to explore the relationship between these two genes and altered triglyceride, Baroukh et al (21) very recently established another apoAI/CIII/ AIV/AV transgenic mouse line and found no differences in triglyceride concentrations between the transgenic and control mice (21). Here we investigate the action of apoCIII and apoAV in triglyceride metabolism via our intact and mutant apoAI gene cluster transgenic mice.…”

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confidence: 91%

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The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

Gao¹,

Wei²,

Huang

et al. 2005

Journal of Biological Chemistry

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The apoAI/CIII/AIV gene cluster is involved in lipid metabolism and has a complex pattern of gene expression modulated by a common regulatory element, the apoCIII enhancer. A new member of this cluster, apolipoprotein (apo) AV, has recently been discovered as a novel modifier in triglyceride metabolism. To determine the expression of all four apo genes in combination and, most importantly, whether the transcription of apoAV is coregulated by the apoCIII enhancer in the cluster, we generated an intact transgenic line carrying the 116-kb human apoAI/CIII/AIV/AV gene cluster and a mutant transgenic line in which the apoCIII enhancer was deleted from the 116-kb structure. We demonstrated that the apoCIII enhancer regulated hepatic and intestinal apoAI, apoCIII, and apoAIV expression; however, it did not direct the newly identified apoAV in the cluster. Furthermore, human apo genes displayed integrated position-independent expression and a closer approximation of copy number-dependent expression in the intact transgenic mice. Because apoCIII and apoAV play opposite roles in triglyceride homeostasis, we analyzed the lipid profiles in our transgenic mice to assess the effects of human apoAI gene cluster expression on lipid metabolism. The triglyceride level was elevated in intact transgenic mice but decreased in mutant ones compared with nontransgenic mice. In addition, the expression of human apoAI and apoAIV elevated high density lipoprotein cholesterol in transgenic mice fed an atherogenic diet. In conclusion, our studies with human apoAI/CIII/ AIV/AV gene cluster transgenic models showed that the apoCIII enhancer regulated expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo and showed the influences of expression of the entire cluster on lipid metabolism.The genes coding apoAI, apoCIII, and apoAIV are clustered within a 17-kb DNA segment on the long arm of human chromosome 11 (1). Comparative sequence analysis recently disclosed a new apolipoprotein (apo) 1 family member, apoAV, located about 30 kb proximal to the apoAI/CIII/AIV gene cluster (2) (Fig. 1). apoAI is the major protein component of HDL. apoAI levels correlate positively with HDL cholesterol and negatively with atherosclerotic cardiovascular diseases (3). Transgenic mice overexpressing human apoAI are protected from diet-related or apoE deficiency-related atherosclerotic lesions (4, 5). apoCIII is the major component of VLDL and a minor component of HDL, and mice carrying human apoCIII develop severe hypertriglyceridemia (6, 7). HDL is a major carrier of plasma apoAIV, and overexpression of human apoAIV decreases aortic lesions in transgenic mice (8, 9). apoAV is found mainly in HDL and VLDL, and human apoAV transgenic mice display ϳ30% triglyceride level compared with wild-type mice (2). In humans, several important single-nucleotide polymorphisms within the apoAI cluster genes have been shown to be strongly associated with dyslipidema and to increase susceptibility to atherosclerosis (10, 11). Recently, such research has focused on associa...

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Section: Discussioncontrasting

confidence: 57%

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confidence: 91%

The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

Gao¹,

Wei²,

Huang

et al. 2005

Journal of Biological Chemistry

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“…However, the exact molecular mechanism underlying the role of APOA5 in triglyceride metabolism remains unclear. The fractional catabolic rate of VLDL and chylomicron triglycerides was markedly accelerated in both human APOA5 transgenic mice and adenovirus-mediated APOA5-overexpressing mice, and was sharply decreased in APOA5-deficient mice, clearly suggesting a role for APOA5 in the hydrolysis of triglycerides [9,10,21,23]. All these studies, however, were complicated by the fact that APOC3, a well-known inhibitor of lipoprotein lipase activity, is decreased in APOA5 transgenic mouse models and increased in APOA5-deficient mice [7].…”

Section: Discussionmentioning

confidence: 99%

Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

et al. 2006

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Aims/hypothesis: Variation in the human apolipoprotein (APO) A5 gene (APOA5) is associated with elevated plasma triglycerides. However, data on the exact role of plasma concentrations of APOA5 in human triglyceride homeostasis are lacking. In the present study, we estimated plasma APOA5 levels in patients with type 2 diabetes at baseline and during atorvastatin treatment, a lipid-lowering treatment that results in a reduction in plasma triglycerides and APOC3. Subjects, materials and methods: Plasma APOA5 concentration was measured by ELISA in 215 subjects with type 2 diabetes, who were taken from the Diabetes Atorvastatin Lipid-lowering Intervention (DALI) study, a 30-week randomised, double-blind, placebo-controlled study, and given atorvastatin 10 mg or 80 mg daily. Results: At baseline, average plasma APOA5 concentration was 25.7±15.6 μg/100 ml. Plasma APOA5 (R s =0.40), APOC3 (R s =0.72) and APOE (R s =0.45) were positively correlated with plasma triglyceride levels (all p<0.001). In multiple linear regression analysis, adjusted for age and sex, the variation in plasma triglycerides was explained mostly by APOC3 (52%) and only to a small extent by APOA5 (6%) and APOE (1%). Atorvastatin treatment decreased plasma triglycerides, APOA5, APOC3 and APOE (all p<0.0001). After treatment, APOC3 remained the major determinant of plasma triglyceride levels (59%), while the contributions of APOA5 and APOE were insignificant (2 and 3%). Conclusions/interpretation: Our findings reveal a positive association between plasma APOA5 and triglycerides in patients with type 2 diabetes. Treatment with atorvastatin decreased plasma APOA5, APOC3, APOE and triglycerides. In contrast to APOC3, APOA5 is not a major determinant of triglyceride metabolism in these patients.

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“…Blood was obtained by retro-orbital bleeding 5 min later, and plasma was frozen at Ϫ80°C. Pre-and post-heparin plasma (5 l) were assayed using an artificial glycerol tri- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]oleate-containing lipid emulsion as described previously (22). To inhibit LPL activity of hepatic lipase, 1 M NaCl was added to independent samples.…”

Section: Methodsmentioning

confidence: 99%

“…A possible effect of apoAV on apoCIII levels is further supported by the fact that human APOA5 transgenic (hAPOA5tr) mice had 40% decreased plasma levels of apoCIII, and apoa5-deficient mice (apoa5Ϫ/Ϫ) had 90% increased plasma levels of apoCIII (4). However, in vitro studies (10) and experiments on mice doubly deficient or transgenic for apoc3 and apoa5 (APOC3 and APOA5) suggested that the apoAV effect on TG levels is at least in part independent of apoCIII (14).…”

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confidence: 99%

Apolipoprotein AV Accelerates Plasma Hydrolysis of Triglyceriderich Lipoproteins by Interaction with Proteoglycan-bound Lipoprotein Lipase

Merkel¹,

Loeffler²,

Kluger³

et al. 2005

Journal of Biological Chemistry

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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. Plasma triglyceride (TG)1 levels are an important independent risk factor for cardiovascular disease susceptibility with both genetic and environmental determinants (1). Among the genetic factors, the contribution of variations at the APOA1/ C3/A4/A5 locus to the determination of TG levels has been well defined (2, 3). APOA5, the newest member of the apolipoprotein family, is located at this locus 27 kb distal (3Ј) to APOA4. It was discovered 3 years ago independently by comparative sequencing (4) and by differential display as a liver regeneration protein (5). Single nucleotide polymorphisms in the APOA5 gene have been associated with differences in human plasma TG levels, familial combined hyperlipidemia, and increased risk of cardiovascular disease (4, 6 -8). Mice expressing a human APOA5 transgene had one-third lower plasma TG levels, whereas knock-out mice lacking apoa5 had four times higher plasma TG levels (4). These data indicate that apoAV plays a major role in the regulation of TG metabolism.However, the molecular mechanism underlying the influence of apoAV on plasma TG is currently not understood. Because apoAV is an apolipoprotein with high lipid affinity and low elasticity, it has been proposed that apoAV may impa...

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

Cited by 74 publications

References 27 publications

The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

Apolipoprotein AV Accelerates Plasma Hydrolysis of Triglyceriderich Lipoproteins by Interaction with Proteoglycan-bound Lipoprotein Lipase

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