Ursodeoxycholic acid aggravates bile infarcts in bile duct–ligated and Mdr2 knockout mice via disruption of cholangioles

Fickert, Peter; Zollner, Gernot; Fuchsbichler, Andrea; Stumptner, Cornelia; Weiglein, Andreas; Lammert, Frank; Marschall, Hanns‐Ulrich; Tsybrovskyy, Oleksiy; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

doi:10.1053/gast.2002.35948

Cited by 292 publications

(284 citation statements)

References 49 publications

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“…Previous results with ursodeoxycholic acidtreated Mdr2 Ϫ/Ϫ mice elegantly demonstrated that an increase in bile acid infarcts upon BDL was a consequence of increased bile flow and subsequently increased intraductal pressures. 28 Results of genetic and pharmacologic manipulation of apoptotic pathways confirm the dominant role of necrosis in BDL-induced liver damage in mice. 29 Thus, we suggest that increased biliary pressure in response to BDL accounts for the increased formation of bile infarcts and liver damage in the Shp Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 86%

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

et al. 2008

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The orphan nuclear hormone receptor small heterodimer partner (SHP) regulates the expression of several genes involved in bile acid homeostasis in the liver. Because bile acid toxicity is a major source of liver injury in cholestatic disease, we explored the role of SHP in liver damage induced by common bile duct ligation (BDL). Shp ؊/؊ mice show increased sensitivity in this model of acute obstructive cholestasis, with greater numbers of bile infarcts and higher mortality than wild-type C57BL/6 mice. This increased sensitivity could not be accounted for by differences in expression of bile acid homeostatic genes 2 or 5 days after BDL. Instead, higher basal expression of such genes, including the key biosynthetic enzyme cholesterol 7␣ hydroxylase (Cyp7A1) and the bile salt export pump, is associated with both an increase in bile flow prior to BDL and an increase in acute liver damage at only 1.5 hours after BDL in Shp ؊/؊ mice, as shown by bile infarcts. At 3 hours, Cyp7A1 expression still remained elevated in Shp ؊/؊ with respect to wild-type mice, and the hepatic and serum bile acid levels and total hepatobiliary bile acid pool were significantly increased. The increased sensitivity of mice lacking SHP contrasts with the decreased sensitivity of mice lacking the farnesoid X receptor (FXR; nuclear receptor subfamily 1, group H, member 4) to BDL, which has been associated with decreased intraductal pressure and fewer bile infarcts. Conclusion: We propose that differences in acute responses to BDL, particularly the early formation of bile infarcts, are a primary determinant of the differences in longer term sensitivity of the Fxr ؊/؊ and Shp ؊/؊ mice to acute obstructive cholestasis. (HEPATOLOGY 2008;

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Section: Discussionmentioning

confidence: 86%

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

et al. 2008

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“…cholestasis parameters, such as alkaline phosphatase and bilirubin, as well as serum bile acid levels (Table 4). To visualize better the bile duct system, plastination casts of the bile ducts were prepared after 4 weeks of DDC treatment, 11 revealing segmental bile duct strictures as well as slight focal dilatation of intrahepatic bile ducts ( Figure 3E). In addition, some pigment plugs were found in the casts.…”

Section: Discussionmentioning

confidence: 99%

A New Xenobiotic-Induced Mouse Model of Sclerosing Cholangitis and Biliary Fibrosis

Fickert

Stöger

Fuchsbichler

et al. 2007

The American Journal of Pathology

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Xenobiotics and drugs may lead to cholangiopathies and biliary fibrosis, but the underlying mechanisms are largely unknown. Therefore, we aimed to characterize the cause and consequences of hepatobiliary injury and biliary fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a novel model of xenobiotic-induced cholangiopathy. Liver morphology, markers of inflammation, cell proliferation, fibrosis, bile formation, biliary porphyrin secretion, and hepatobiliary transporter expression were studied longitudinally in DDC-and control dietfed Swiss albino mice. DDC feeding led to increased biliary porphyrin secretion and induction of vascular cell adhesion molecule, osteopontin, and tumor necrosis factor-␣ expression in bile duct epithelial cells. This was associated with a pronounced pericholangitis with a significantly increased number of CD11b-positive cells, ductular reaction, and activation of periductal myofibroblasts, leading to large duct disease and a biliary type of liver fibrosis. After 4 weeks, we constantly observed intraductal porphyrin pigment plugs. Glutathione and phospholipid excretion significantly decreased over time. Expression of Ntcp, Oatp4, and Mrp2 was significantly reduced, whereas Bsep expression remained unchanged and adaptive Mrp3 and Mrp4 expression was significantly induced. We demonstrate that DDC feeding in mice leads to i) a reactive phenotype of cholangiocytes and bile duct injury, ii) pericholangitis, periductal fibrosis, ductular reaction, and consequently portal-portal bridging , iii) down-regulation of Mrp2 and impaired glutathione excretion , and iv) segmental bile duct obstruction. This model may be valuable to investigate the mechanisms of xenobiotic-induced chronic cholangiopathies and its sequels including biliary fibrosis.

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“…34 However, its choleretic action also increases biliary pressure, which has been shown to aggravate bile infarcts and hepatocyte necrosis in the homozygous Mdr2Ϫ/Ϫ mice. 15 Moreover, ursodeoxycholic acid also displays a toxic character, affecting mitochondrial activity. 10 Alternatively, the administration of fibrates, statins, or peroxisome proliferators, which all have been shown to induce biliary phospholipid secretion by the induction of Mdr2, making bile less toxic, might pose a therapeutic approach to prevent bile duct complications after OLT .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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Ursodeoxycholic acid aggravates bile infarcts in bile duct–ligated and Mdr2 knockout mice via disruption of cholangioles

Cited by 292 publications

References 49 publications

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis

A New Xenobiotic-Induced Mouse Model of Sclerosing Cholangitis and Biliary Fibrosis

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

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