ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice

Vaisman, Boris; Lambert, Gilles; Amar, Marcelo; Joyce, Charles; Ito, Tsuyoshi; Shamburek, Robert D.; Cain, William J.; Fruchart‐Najib, Jamila; Neufeld, Edward D.; Remaley, Alan T.; Brewer, H. Bryan; Santamarina-Fojo, Silvia

doi:10.1172/jci12517

Cited by 119 publications

(142 citation statements)

References 46 publications

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“…The results of the present investigation suggest that variants of ABCA1 primarily affect APOB levels given that there was no evidence for effects upon HDL-C or APOA1 levels, the two principal phenotypes for which several prior studies suggest association (Wang et al 2000;Srinivasan et al 2003;Tregouet et al 2004). Studies in animal models point to several phenotypes that are affected by ABCA1 modification, including plasma APOB levels, which has been shown both in transgenic mice (Vaisman et al 2001) and more recently in studies exploiting RNA interference (Ragozin et al 2005). In the present study, significant effects were also evident for LDL-C and TC levels, but this is perhaps unsurprising given the strong correlations of these traits with APOB.…”

Section: Discussionsupporting

confidence: 44%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of b-amyloid (Ab) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab 1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Ab 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDLcholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus nonsmokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Ab and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

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Section: Discussionsupporting

confidence: 44%

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Katzov

Bennet

Höglund³

et al. 2005

J Hum Genet

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“…Generation of ABCG5/G8 Transgenic Mice-A fully characterized and sequenced 140-kb BAC clone (BAC 26313; Incyte Genomics, Palo Alto, CA) encoding the complete ABCG5 and ABCG8 proteins (28) was used to generate transgenic mice in the C57Bl/6 background as described (29). Integration of the hABCG5/G8 genes was determined by dot blot hybridization analysis of genomic mouse tail DNA using fulllength hABCG5/G8 cDNA probes and confirmed by PCR using humanspecific ABCG5/G8 primers (sequences available upon request).…”

Section: Methodsmentioning

confidence: 99%

“…Analyses of Plasma Lipids-Plasma was obtained after a 4-hour fast and lipid levels were determined as previously described (29,32). HDLcholesterol (HDL-C) was determined as the cholesterol remaining in the plasma after precipitation of the apoB-containing lipoproteins with heparin-calcium (Ciba-Corning, OH) or dextran-sulfate (Bayer Corp. Tarrytown, NY).…”

Section: Methodsmentioning

confidence: 99%

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Basso

Shamburek

et al. 2004

Journal of Biological Chemistry

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The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by ϳ25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.Sitosterolemia, also known as phytosterolemia (1-9) is a rare genetic disorder characterized by elevated plasma and tissue levels of plant, shellfish, and animal sterols and the development of tendon and tuberous xanthomas, hemolytic episodes, arthritis, and premature coronary artery disease. The ATPbinding cassette (ABC) 1 half-transporters ABCG5 and ABCG8 (ABCG5/G8) have been recently identified as the genes defective in sitosterolemia (10 -12). The increased plasma and tissue levels of animal and plant sterols found in sitosterolemic patients have been attributed to enhanced absorption and decreased biliary excretion (1-4, 6, 8, 13-16). Unlike cholesterol, sitosterol accumulation does not inhibit HMGCoA reductase activity in human monocyte-derived macrophages (17). The inadequate down-regulation of HMGCoA reductase activity by plant sterols may promote foam cell formation and explain, in part, the increased risk of atherosclerosis in sitosterolemia (17).Several lines of evidence implicate ABCG5/G8 in intestinal and biliary sterol transport. First, ABCG5/G8 are expressed in the liver and small intestine and, to a lesser degree, in th...

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“…mary hepatocytes from ABCA1-deficient mice compared with its wild type counterpart. Brewer and colleagues have shown convincingly that specific overexpression of ABCA1 in the liver was sufficient to increase HDL cholesterol in mice (29,47). Interestingly, overexpression of ABCA1 in the liver through adenovirus resulted in not only HDL cholesterol increase but also an increase in HDL particle size (47).…”

Section: Figmentioning

confidence: 99%

“…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). It has also been reported that apoE plays an obligatory role in large HDL formation (20).…”

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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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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ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice

Cited by 119 publications

References 46 publications

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

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

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