Biliary Anionic Peptide Fraction/Calcium Binding Protein Inhibits Apolipoprotein A-I-Mediated Cholesterol Efflux from Cultured Cells

Wijland, M.J.A. van; Waart, Dirk R. de; Groen, Albert K.

doi:10.1006/bbrc.2001.5542

Cited by 7 publications

(6 citation statements)

References 20 publications

(23 reference statements)

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“…One possibility is that this is a defence mechanism that allows the GB to unload excessive amounts of absorbed cholesterol and phospholipid, the majority of which enters the cell passively [3]. This may be relevant for cholesterol gallstone formation, as inhibition of ABCA1-mediated cholesterol efflux by the pro-nucleating anionic peptide fraction\calcium-binding protein, which shares sequence homology with apoA-I, has been demonstrated [48]. The roles of other ABC transporters, nuclear hormone receptors, endogenous apolipoproteins and scavenger-receptor class B type I in mediating cholesterol transport in GBEC remain to be defined.…”

Section: Discussionmentioning

confidence: 99%

Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway

Liu

Shirk

Oram

et al. 2002

Biochemical Journal

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Gall-bladder epithelial cells (GBEC) are exposed to high concentrations of cholesterol in bile. Whereas cholesterol absorption by GBEC is established, the fate of this absorbed cholesterol is not known. The aim of this study was to determine whether ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux in GBEC. Polarized canine GBEC were cultured on porous membrane filters allowing separate access to apical (AP) and basolateral (BL) compartments. After AP loading of cells with model bile and [14C]cholesterol, cholesterol efflux was measured. Cholesterol loading together with 8-bromo-cAMP treatment, which increased ABCA1 expression, led to a significant increase in cholesterol efflux with apolipoprotein A-I (apoA-I) as the acceptor. Cholesterol efflux was observed predominantly into the BL compartment. Similar results were found for phospholipid efflux. Confocal immunofluorescence microscopy showed a predominantly BL ABCA1 localization. Interestingly, apoA-I added to either the AP or the BL compartments elicited BL lipid efflux with cAMP treatment. No paracellular or transcellular passage of 125I-apoA-I occurred. Ligands for the nuclear hormone receptors liver X receptor alpha (LXRalpha) and retinoid X receptor (RXR) elicited AP and BL cholesterol efflux, suggesting the involvement of both ABCA1- and non-ABCA1-mediated pathways. In summary, BL cholesterol/phospholipid efflux consistent with an ABCA1-mediated mechanism occurs in GBEC. This efflux pathway is stimulated by cAMP and by LXRalpha/RXR ligands, and in the case of the cAMP pathway appears to involve a role for biliary apoA-I.

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Section: Discussionmentioning

confidence: 99%

Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway

Liu

Shirk

Oram

et al. 2002

Biochemical Journal

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“…Cholesterol efflux assays were performed as described. 20 In short, dog gallbladder epithelial cells were grown for 5 days until confluency in collagen-coated 24-well plates in Dulbecco's modified eagle medium and 10% fetal calf serum in the presence of 2 g/mL diosgenin or vehicle (ethanol; final concentration, 0.4%). Cells were loaded with [ 3 H]cholesterol by incubation for 24 hours with Dulbecco's modified eagle medium supplemented with 30 g/mL cholesterol, 0.5 Ci/mL [ 3 H]cholesterol, 10 mM Hepes pH 7.4, and 0.2% fatty acid-free bovine serum albumin.…”

Section: Methodsmentioning

confidence: 99%

Diosgenin-induced biliary cholesterol secretion in mice requires Abcg8

Kosters¹,

Frijters²,

Kunne³

et al. 2005

Hepatology

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The plant sterol diosgenin has been shown to stimulate biliary cholesterol secretion in mice without affecting the expression of the adenosine triphosphate-binding cassette transporter heterodimer Abcg5/g8. The aim of this study was to investigate the mechanism of diosgenininduced cholesterol hypersecretion and to identify the genes involved. Surprisingly, despite its lack of effect on Abcg5/g8 expression in wild-type mice, diosgenin did not stimulate biliary cholesterol secretion in mice deficient for Abcg8. Analysis of the kinetics of cholesterol secretion suggested that diosgenin probably activates a step before Abcg5/g8. To identify potential diosgenin targets, gene expression profiling was performed in mice fed a diosgeninsupplemented diet. Diosgenin feeding increased hepatic expression of genes involved in cholesterol synthesis as well as genes encoding for several cytochrome P450s. No significant change in expression of known cholesterol transporters was found. Comparison with published expression-profiling data for Srebp2-overexpressing mice, another mouse model in which biliary cholesterol secretion is elevated, revealed a number of genes with unknown function that were upregulated in both diosgenin-fed mice and mice overexpressing Srebp2.In conclusion, we found that although Abcg8 is essential for most diosgenin-induced biliary cholesterol hypersecretion, diosgenin probably does not interact directly with Abcg5/Abcg8, but rather increases cholesterol delivery to the heterodimer. T he human liver secretes approximately 1 g of cholesterol per day into the bile. Most of this cholesterol is taken up from the blood in the form of lipoproteins. The pathways involved in transhepatic cholesterol trafficking into bile are still largely unknown. A number of intracellular proteins such as Niemann Pick C 1 and 2, sterol carrier protein 2, liver-type fatty acid binding protein, Rab9, and caveolins have been implicated, but their quantitative importance is unknown (see for review Soccio and Breslow 1 and Ory 2 ). After arrival at the canalicular membrane of the hepatocyte, cholesterol is secreted into the bile. It has long been assumed that biliary cholesterol secretion was not protein mediated. This concept changed with the discovery of the adenosine triphosphate-binding cassette half transporters ABCG5 and ABGG8. Patients with mutations in either of these genes show increased intestinal absorption of sterols as well as decreased biliary sterol secretion, suggesting a primary role of these transporters in plant sterol metabolism as well as in cholesterol transport. [3][4][5] The important role of Abcg5/g8 in biliary cholesterol output was confirmed in mice overexpressing human ABCG5/G8 or in mice lacking both genes, indicating that most biliary cholesterol secretion is mediated by Abcg5/g8. 6,7 However, it should be noted that 10% to 30% of biliary cholesterol secretion is independent of Abcg5/g8 activity. [7][8][9] We recently showed in a variety of mouse models that the hepatic

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“…Cholesterol efflux was measured as described by van Wijland et al [19]. In brief, cholesterol loading was performed by incubating DGBE for a period of 20 h with DMEM supplemented with 0.5 lCi/ml [ 3 H]cholesterol, and 0.2% fatty acid free BSA.…”

Section: Cholesterol Efflux Assaymentioning

confidence: 99%

The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux

et al. 2007

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The ATP binding cassette transporters ABCG5 and ABCG8 are indispensable for hepatobiliary cholesterol transport. In this study, we investigated the specificity of the heterodimer for cholesterol acceptors. Dog gallbladder epithelial cells were mono-or double-transfected with lentiviral mouse Abcg5 and Abcg8 vectors. Double-transfected cells showed increased efflux to different bile salt (BS) species, while mono-transfected cells did not show enhanced efflux. The efflux was initiated at micellar concentrations and addition of phosphatidylcholine increased efflux. Cholesterol secretion was highly BS dependent, whereas other cholesterol acceptors such as ApoAI, HDL or methyl-b-cyclodextrin did not elicit Abcg5/g8 dependent cholesterol secretion.

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Biliary Anionic Peptide Fraction/Calcium Binding Protein Inhibits Apolipoprotein A-I-Mediated Cholesterol Efflux from Cultured Cells

Cited by 7 publications

References 20 publications

Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway

Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway

Diosgenin-induced biliary cholesterol secretion in mice requires Abcg8

The sterol transporting heterodimer ABCG5/ABCG8 requires bile salts to mediate cholesterol efflux

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