High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1

McNeish, John D.; Aiello, Robert J.; Guyot, Deborah J.; Turi, Tom; Gabel, Christopher A.; Aldinger, Charles E.; Hoppe, Kenneth L.; Roach, Marsha L.; Royer, Lori; Wet, Jeffery de; Broccardo, Cyril; Chimini, Giovanna; Francone, Omar L.

doi:10.1073/pnas.97.8.4245

Cited by 500 publications

(409 citation statements)

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“…ABCA1 deficiency leads to a near total absence of HDL cholesterol both in humans and mice (22)(23)(24)(25)(26)(27). The molecular mechanisms of ABCA1 contributing to the HDL biogenesis, however, may need further refinement.…”

Section: Resultsmentioning

confidence: 99%

“…The enlargement of HDL after LXR agonist administration to mice may largely involve the induction of ABCA1 and apoE, since both gene products are intimately involved in HDL metabolism and are regulated by LXRs (10,11,21). ABCA1 deficiency causes hypoalphalipoproteinemia in humans (22-25) and mice (26,27). ABCA1 overexpression in mice leads to an increased plasma HDL cholesterol level (28,29).…”

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confidence: 99%

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Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

Jiang

Beyer

Liu

et al. 2003

Journal of Biological Chemistry

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The factors involved in the generation of larger high density lipoprotein (HDL) particles, HDL 1 and HDL c , are still not well understood. Administration of a specific synthetic liver X receptor (LXR) agonist, T0901317, in mice resulted in an increase of not only HDL cholesterol but also HDL particle size (Cao, G., Beyer, T. P., Yang, X. P., Schmidt, R. J., Zhang, Y., Bensch, W. R., Kauffman, R. F., Gao, H., Ryan, T. P., Liang, Y., Eacho, P. I., and Jiang, X. C. (2002) J. Biol. Chem. 277, 39561-39565). We have investigated the roles that apoE and CETP may play in this process. We treated apoE-deficient, cholesterol ester transport protein (CETP) transgenic, and wild type mice with various doses of the LXR agonist and monitored their HDL levels. Fast protein liquid chromatography and apolipoprotein analysis revealed that in apoE knockout mouse plasma, there was neither induction of larger HDL formation nor increase of HDL cholesterol, suggesting that apoE is essential for the LXR agonist effects on HDL metabolism. In CETP transgenic mice, CETP expression completely abolished LXR agonist-mediated HDL enlargement and greatly attenuated HDL cholesterol levels. Analysis of HDL particles by electron microscope and nondenaturing gel electrophoresis revealed similar findings. In apoE-deficient mice, LXR agonist also produced a significant increase in very low density lipoprotein/low density lipoprotein cholesterol and apolipoprotein B content. Our studies provide direct evidence that apoE and CETP are intimately involved in the accumulation of the enlarged HDL (HDL 1 or HDL c ) particles in mice.Epidemiological studies have firmly established that plasma HDL 1 cholesterol is inversely correlated to coronary artery events (1). The biogenesis of HDL is thought to originate from the secretion of its major apolipoprotein component, apoAI, from the liver and the small intestine. ApoAI enters the circulation and interacts with and removes excessive free cholesterol from peripheral tissues, forming disc-like nascent HDL particles. ApoAI-dependent phospholipid and cholesterol efflux from peripheral tissues requires the protein ABCA1, an ATP binding cassette transporter (2). The maturation of HDL depends on both lecithin-cholesterol acyltransferase and phospholipid transfer protein (PLTP) activities. The former esterifies free cholesterol to form spherical HDL (3), and the latter transfers phospholipid from triglyceride-rich lipoproteins into the nascent HDL particles (4). Cholesteryl ester transfer protein (CETP) catalyzes transfer of cholesteryl ester from mature HDL into apoB-containing lipoproteins for catabolism through liver low density lipoprotein receptor (LDLR) (5). HDL cholesterol can also be delivered to the liver via scavenger receptor BI, the HDL receptor, through the process of selective cholesterol uptake (6). It is conceivable that the regulation of ABCA1, lecithin-cholesterol acyltransferase, PLTP, CETP, and scavenger receptor BI would have an important impact on HDL metabolism, including particle catabolic rat...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

Jiang

Beyer

Liu

et al. 2003

Journal of Biological Chemistry

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“…ABCA1 mediates the efflux of cellular phospholipids and free cholesterol to extracellular acceptors, namely lipid-free or lipid-poor apoA-I, producing pre-β HDL particles (Francis et al 1995;Rogler et al 1995;Brewer et al 2004;Lee and Parks 2005;. The significant role of ABCA1 in HDL formation is underscored by the finding that mutations in Abca1 lead to near absence of plasma HDL-C concentrations in patients with Tangier disease (Oram 2000) and Abca1 knockout mice (Schreyer et al 1994;McNeish et al 2000;Francone et al 2003). Interaction of apoA-I with ABCA1 produces heterogeneous-sized, pre-β migrating nascent HDL subpopulations (pre-β1 to pre-β4) that vary in size, lipid, and apoA-I content in vitro and have different metabolic fates with less lipidated pre-β HDL being rapidly removed from the circulation without participating in RCT (Mulya et al 2007(Mulya et al , 2008.…”

Section: Introductionmentioning

confidence: 87%

High-density lipoprotein metabolism in human apolipoprotein B₁₀₀transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

Ehlers

Larson

Rasmussen

et al. 2011

Appl. Physiol. Nutr. Metab.

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Obese and diabetic humans display decreased plasma high-density lipoprotein cholesterol (HDL-C) concentrations and an increased risk for coronary heart disease. However, investigation on HDL metabolism in obesity with a particular emphasis on hepatic ATP-binding cassette transporter A1 (ABCA1), the primary factor for HDL formation, has not been well studied. Human apolipoprotein B100 transgenic (hApoB tg ) and brown adipose tissue deficient (BATless) mice were crossed to generate hApoB tg /BATless mice. Male and female hApoB tg and hApoB tg /BATless mice were maintained on either a regular rodent chow diet or a diet high in fat and cholesterol until 24 weeks of age. The hApoB tg /BATless mice that were fed a HF/HC diet became obese, developed hepatic steatosis, and had significantly elevated plasma insulin levels compared with their hApoB tg counterparts, but plasma concentrations of total cholesterol, HDL-C, triglycerides, and free fatty acids and lipoprotein distribution between genotypes were not significantly different. Hepatic expression of genes encoding HDL-modifying factors (e.g., scavenger receptor, class B, type I, hepatic lipase, lecithin:cholesterol acyltransferase, and phospholipid transfer protein) was either altered significantly or showed a trend 3 6 (2 0 1 1 ) 2 of difference between 2 genotypes of mice. Importantly, hepatic protein levels of ABCA1 were significantly lowered by ∼35% in male obese hApoB tg /BATless mice with no difference in mRNA levels compared with hApoB tg counterparts. Despite reduced hepatic ABCA1 protein levels, plasma HDL-C concentrations were not altered in male obese hApoB tg /BATless mice. The result suggests that hepatic ABCA1 may not be a primary contributing factor for perturbations in HDL metabolism in obesityinduced hyperinsulinemia. , A P P L I E D P H Y S I O L O G Y , N U T R I T I O N , A N D M E T A B O L I S M

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“…À l'inverse, l'activation de LXR induit l'expression de ABCA1 dans des lignées de cellules , les MIN6, et stimule la sécrétion d'insuline dans des îlots isolés de rat [8]. Des études menées chez la souris montrent que l'invalidation de ABCA1 dans l'ensemble des tissus entraîne une intolérance au glucose mais est sans effet sur la sensibilité à l'insuline [10]. Lorsque l'invalidation d'ABCA1 est restreinte aux seules cellules , il n'y a pas d'altération systémique SYNTHÈSE REVUES un grand nombre de modèles cellulaires : cultures primaires d'îlots et de cellules  isolés de tissus humains et de rongeurs (rat et souris) [13,14], ou lignées tumorales de souris comme MIN-6 et TC3 [14], de rat comme les INS-1 [15] ou encore de hamster, les HIT-15 [16].…”

Section: Rôle Des Lipoprotéines Et Du Récepteur Au Ldl Sur La Fonctiounclassified

Métabolisme du cholestérol et function β-cellulaire

Langhi

Cariou

2010

Med Sci (Paris)

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L'incidence du diabète de type 2 (DT2) atteint des proportions épidémiques ces dernières années en raison du vieillissement de la population et du développement de l'obésité, elle-même secondaire à l'augmentation de la sédentarité et à une alimentation trop riche en graisses. L'insulinorésistance est un événement précoce dans la physiopathologie du DT2, mais qui demeure relativement stable au cours de l'évolution de la maladie. À l'inverse, la capacité insulinosécrétrice de la cellule  pancréatique diminue au cours du temps et contribue de façon majoritaire à la détérioration progressive de l'équilibre glycémique chez les diabétiques de type 2 [1]. Étant donné que la carence fonctionnelle de la cellule  est potentiellement réversible, il apparaît important de développer des thérapeutiques visant à freiner cette insuffisance [2]. Un des mécanismes moléculaires les mieux étudiés actuellement est la lipotoxicité bêta-pancréatique, qui contribue, via l'accumulation intracellulaire de lipides, à l'altération de l'insulinosécrétion et au développement de l'apoptose [3,4]. Les espèces lipidiques incriminées sont essentiellement les acides gras libres circulants (notamment le palmitate) et les triglycérides, qui favorisent la mort de la cellule  en induisant la production de céramides cytotoxiques [3]. Plus récemment, des données suggè-rent que le cholestérol pourrait également jouer un rôle majeur dans le contrôle de la fonction cellulaire . Nous discuterons en détail ici les différents liens potentiels entre le métabolisme du cholestérol et le contrôle de l'insulinosécrétion. Le cholestérol intracellulaire : un nouvel acteur de l'insulinosécrétionPlusieurs approches expérimentales ont permis d'étu-dier la conséquence des variations de cholestérol intracellulaire sur la sécrétion d'insuline.Rôle de la synthèse de cholestérol intracellulaire SREBP2 (sterol response element binding protein-2) est un facteur de transcription qui régule les concentrations du cholestérol intracellulaire. En réponse à une baisse du cholestérol intracellulaire, SREBP2 stimule la synthèse endogène de cholestérol ainsi que la capture des LDL (low density lipoproteins) en augmentant > Le diabète de type 2 est fréquemment associé à une dyslipidémie mixte, ainsi qu'à une lipotoxicité caractérisée par une augmentation du contenu en triglycérides dans plusieurs types cellulaires. Au niveau de la cellule -pancréatique, cette lipotoxicité conduit à un défaut d'insulinosécrétion et à une apoptose. Plus récemment, de nouvelles données suggèrent l'existence d'un lien entre le métabolisme du cholestérol et la fonction des cellules . Ainsi, l'accumulation de cholestérol dans les îlots pancréatiques altère la sécrétion d'insuline. Sur le plan moléculaire, le transporteur ABCA1 (ATP-binding cassette transporter, member 1) et le récepteur des LDL (low density lipoproteins) apparaissent comme des médiateurs majeurs du métabolisme du cholestérol dans l'îlot. Le cholestérol intracellulaire semble réguler à la fois l'organisation des microdomaines membranai...

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High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1

Cited by 500 publications

References 32 publications

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

High-density lipoprotein metabolism in human apolipoprotein B₁₀₀transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

Métabolisme du cholestérol et function β-cellulaire

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High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1

Cited by 500 publications

References 32 publications

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

High-density lipoprotein metabolism in human apolipoprotein B100transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

Métabolisme du cholestérol et function β-cellulaire

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High-density lipoprotein metabolism in human apolipoprotein B₁₀₀transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia