Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice

Fickert, Peter; Fuchsbichler, Andrea; Wagner, Martin; Zollner, Gernot; Kaser, Arthur; Tilg, Herbert; Krause, Robert; Lammert, Frank; Langner, Cord; Zatloukal, Kurt; Marschall, Hanns‐Ulrich; Denk, Helmut; Trauner, Michael

doi:10.1053/j.gastro.2004.04.009

Cited by 425 publications

(421 citation statements)

References 47 publications

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“…Nevertheless, we did not observe increased paracellular permeability related to disrupted tight junctions and basement membranes as described in the Mdr2Ϫ/Ϫ mice by Fickert et al 16 However, unlike Mdr2Ϫ/Ϫ livers, liver grafts of Mdr2ϩ/Ϫ donors were not exposed to such high levels of toxic non-micellarbound bile salts after transplantation, as they still excrete some phospholipids. Moreover, the initially high biliary bile salt/phospholipid ratio in Mdr2ϩ/Ϫ liver grafts turned normal after 14 days due to cholestasis and reduced bile salt excretion.…”

Section: Discussioncontrasting

confidence: 46%

“…11,12 Mice homozygous for the disruption of the multidrug resistance 2 Mdr2 gene (Abcb4), a homologue of human MDR3, completely lack phospholipids in their bile and develop progressive bile duct injury and cholestasis early in life. 13,14 Based on the development of intrahepatic biliary strictures, these animals have been proposed as a model for sclerosing cholangitis 15,16 and also share many features of the non-anastomotic strictures observed after OLT.…”

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confidence: 99%

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Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

et al. 2006

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Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2؉/؊) were transplanted into wild-type recipient mice. Mdr2؉/؊ mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2 ؊/؊ mice, the Mdr2؉/؊ mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2؉/؊ donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2؉/؊ livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2؉/؊ grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation. (HEPATOLOGY 2006;43:1022-1031

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Section: Discussioncontrasting

confidence: 46%

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confidence: 99%

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

et al. 2006

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“…Here, we investigated the effect of tannic acid and selenomethionine, supplemented during prenatal period and first 3 months of life, on liver tumor development in the Mdr2-KO mice that represent an inflammation-associated hepatocellular carcinoma model. These mice develop non-suppurative inflammatory cholangitis during the first 3 months, which is characterized by bile acid leakage into portal tracts, increased bile ducts proliferation, and portal inflammation (5,9). Recently, we have shown induction of antioxidant protection systems and stimulation of hepatocyte DNA replication in the liver of Mdr2-KO mice at the age of 3 months (7).…”

Section: Discussionmentioning

confidence: 99%

“…The Mdr2-KO mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the bile canalicular membrane (8). The absence of phospholipids from bile results in bile regurgitation (9) and portal inflammation followed by the development of hepatocyte dysplasia and hepatocellular carcinoma (5). We have recently shown induction of multiple protective mechanisms in the livers of Mdr2-KO mice at 3 months of age, particularly, the induction of antioxidant protective systems (7).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Therapeutics

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Dietary antioxidants and selenium compounds were shown to have a therapeutic effect against hepatocellular carcinoma in several mouse models. We tested the effects of tannic acid and selenomethionine on hepatocellular carcinoma development in Mdr2 knockout (Mdr2-KO) mice. Mdr2-KO and age-matched Mdr2 heterozygous control mice were fed with tannic acid or selenomethionine during the first 3 months of life. Then, several mice from each group were sacrificed, and liver tissue samples were removed for analysis. The remaining mice were fed a regular diet until the age of 16 months, at which time the number and size of liver tumors were determined. Liver tissue samples of 3-month-old mice were subjected to gene expression profiling analysis using cDNA macroarrays containing probes for 240 genes that regulate responses to oxidative stress and inflammation or lipid metabolism. Both tannic acid and selenomethionine had partial chemopreventive effect on development of hepatocellular carcinoma in Mdr2-KO mice: they reduced the incidence of large tumor nodules (diameter >1 cm) at age 16 months. Both agents inhibited gene expression and reversed up-regulation of many genes that control inflammation or response to oxidative stress in Mdr2-KO livers at age 3 months. This inhibitory effect on gene expression correlated with the ability of agents to reduce incidence of large tumors: selenomethionine was more active than tannic acid in both aspects. Understanding the molecular mechanism of chemoprevention effect could improve our therapeutic modalities while using these agents. [Mol Cancer Ther 2007;6(4):1283 -91]

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“…Still, liver failure does not occur during the lifespan of these animals. 11,15 Overall, these mouse models display much less severe phenotypes compared with those of human patients. 11,12 A likely explanation for this discrepancy may be the difference in bile salt pool composition.…”

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confidence: 99%

Hepatic cytochrome P450 deficiency in mouse models for intrahepatic cholestasis predispose to bile salt-induced cholestasis

Kunne

Graaff

Duijst

et al. 2014

Laboratory Investigation

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Progressive familial intrahepatic cholestasis (PFIC) types 1 and 3 are severe cholestatic liver diseases caused by deficiency of ATB8B1 and ABCB4, respectively. Mouse models for PFIC display mild phenotypes compared with human patients, and this can be explained by the difference in bile salt pool composition. Mice, unlike humans, have the ability to detoxify hydrophobic bile salts by cytochrome P450-mediated (re)hydroxylation and thus have a less toxic bile salt pool. We have crossed mouse models for PFIC1 and PFIC3 with Hrn mice that have a reduced capacity to (re)hydroxylate bile salts. Double transgenes were obtained by backcrossing Atp8b1 G308V/G308V and Abcb4 À / À mice with Hrn mice that have a liverspecific disruption of the cytochrome P450 reductase gene and therefore have markedly reduced P450 activity. In these mice, a more hydrophobic bile salt pool was instilled by cholic acid supplementation of the diet, and bile formation and liver pathology was studied. As opposed to single transgenes, Atp8b1 G308V/G308V /Hrn and Abcb4 À / À /Hrn mice rapidly developed strong cholestasis that was evidenced by increased plasma bilirubin and bile salt levels. The bile salt pool was more toxic in both models; Atp8b1 G308V/G308V /Hrn mice had a more hydrophobic plasma pool compared with the single transgene, whereas Abcb4 À / À /Hrn mice had a more hydrophobic biliary pool compared with the single transgene. In line with these findings, liver damage was not aggravated in Atp8b1 G308V/G308V /Hrn but was more severe in Abcb4 À / À /Hrn mice. These data indicate that bile salt pool composition is a critical determinant in the initiation and progression of cholestasis and liver pathology in PFIC1 and PFIC3. Most importantly, our data suggest that the hydrophobicity of the plasma bile salt pool is an important determinant of the severity of cholestasis, whereas the hydrophobicity of the biliary bile salt pool is an important determinant of the severity of liver pathology.

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Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice

Cited by 425 publications

References 47 publications

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice

Hepatic cytochrome P450 deficiency in mouse models for intrahepatic cholestasis predispose to bile salt-induced cholestasis

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