Protective role of biliary cholesterol and phospholipid lamellae against bile acid-induced cell damage

Puglielli, Luigi; Amigo, Ludwig; Arrese, Marco; Núñez, L; Rigotti, Attilio; Garrido, Jorge; González, Sergio; Mingrone, Geltrude; Greco, Aldo V.; Accatino, Luigi; Nervi, Flavio

doi:10.1016/0016-5085(94)90083-3

Cited by 65 publications

(41 citation statements)

References 46 publications

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“…Vesicle transport has been implicated, and diosgenin has been shown to increase the content of intracellular vesicles located near the canalicular membrane. 34 However, the genes on the array encoding proteins involved in vesicle transport from and to the apical membrane showed no change in expression. In addition to vesicular transport, cytoplasmic proteins like liver fatty acid-binding protein, sterol carrier protein-2, caveolin-1 and -2, and Niemann Pick C 1 and 2 proteins have been suggested to play a role in the intracellular transport and biliary CH secretion.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

Diosgenin-induced biliary cholesterol secretion in mice requires Abcg8

Kosters¹,

Frijters²,

Kunne³

et al. 2005

Hepatology

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“…Several dietary or pharmacological manipulations may modify and uncouple the rate of biliary phospholipid secretion from bile acid secretion [26,45]. We have previously shown that colchicine selectively induces the mdr2 gene and its encoded P-gp in mouse liver [27], even though colchicine, like other agents that affect microtubular polymerization, greatly reduce biliary lipid secretion [46].…”

Section: Discussionmentioning

confidence: 99%

“…In some experiments, liver samples were taken for morphological and immunohistochemical analysis. Biliary cholesterol, phospholipids and bile acids were quantified [25], and biliary bile acid pool composition was estimated by HPLC as previously described [26].…”

Section: Bile and Liver Samplingmentioning

confidence: 99%

Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse

Chianale

Vollrath

Wielandt

et al. 1996

Biochemical Journal

Self Cite

144

109

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Disruption of the murine mdr2 gene leads to the complete absence of biliary phospholipids. We tested the hypothesis that the increase in biliary phospholipid output induced by fibrates is mediated via induction of the hepatic mdr2 gene and its encoded product, the P-glycoprotein canalicular flippase. Increased levels of mdr2 mRNA were observed in the liver of mice treated with different fibrates : ciprofibrate, 660p155 % (as compared with control group) ; clofibrate, 611p77 % ; bezafibrate, 410p47 % ; fenofibrate, 310p52 % ; gemfibrozil, 190p25 % (P 0n05 compared with control group). Induction of expression of the mdr gene family was specific to the mdr2 gene. Two-to three-fold increases in P-glycoprotein immunodetection were evident on the canalicular plasma-membrane domain of clofibrate-and ciprofibrate-treated mice. Biliary phospholipid output increased

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“…Liposomes composed of cholesterol, phosphatidylcholine, phosphatidylserine and lactosylceramide (10 : 8 : 2 : 2, molar ratio) were dissolved in chloroform\methanol (2 : 1, v\v), evaporated under nitrogen and stored at k20 mC as described [15]. Samples (40 µg) of the dried lipids were resuspended in 1.5 ml of PBS (pH 7.2), containing 1 mg\ml of the oligonucleotides, by gentle vortexing and brief sonication pulses (15-30 s) in a bath-type sonicator [21]. The oligonucleotide dose was chosen based on previous reports from other groups [22][23][24].…”

Section: Preparation Of Liposomes and Incorporation Of Scp-2 Antisensmentioning

confidence: 99%

“…Densitometric analysis of Northern blots of SCP-2 was performed with a CS-900 Scanner (Shimadzu Corporation, Kyoto, Japan) using the β-2 microglobulin blot as denominator. [21] determinations, respectively, and visualized with I # vapour. Spots were scraped and counted in a liquid scintillation counter to reach 10 000 counts [16].…”

Section: Northern Blot Analysesmentioning

confidence: 99%