Development of an experimental model of cholestasis induced by hypoxic/ischemic damage to the bile duct and liver tissues in infantile rats

Toki, Fumiaki; Takahashi, Atsushi; Suzuki, Makoto; Ootake, Sayaka; Hirato, Junko; Kuwano, Hiroyuki

doi:10.1007/s00535-010-0330-5

Cited by 4 publications

(5 citation statements)

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“…Tissue hypoxia in the liver can be caused by several forms of liver injury . In cholestasis the toxic effect of bile acids within hepatocytes is prevented by adaptive responses such as induction of bile acid efflux transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Various conditions can cause hypoxia or induce hypoxia modulators, such as ischaemia, ischaemic reperfusion injury, cancer and inflammation. In addition, cholestasis induces hypoxia in the liver and low oxygen levels regulate bile salt transporters. However the exact mechanism by which hypoxia modulates the expression of these transport proteins has not been elucidated.…”

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confidence: 99%

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The organic solute transporters alpha and beta are induced by hypoxia in human hepatocytes

Schaffner

Mwinyi

Gai

et al. 2014

Liver International

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Background & AimsThe organic solute transporters alpha and beta (OSTα-OSTβ) form a heterodimeric transporter located at the basolateral membrane of intestinal epithelial cells and hepatocytes. Liver injury caused by ischaemia-reperfusion, cancer, inflammation or cholestasis can induce a state of hypoxia in hepatocytes. Here, we studied the effect of hypoxia on the expression of OSTα-OSTβ.MethodsOSTα-OSTβ expression was measured in Huh7 cells and primary human hepatocytes (PHH) exposed to chenodeoxycholic acid (CDCA), hypoxia or both. OSTα-OSTβ promoter activity was analysed in luciferase reporter gene assays. Binding of hypoxia-inducible factor-1 alpha (HIF-1α) to the OSTα-OSTβ gene promoters was studied in electrophoretic mobility shift assays (EMSA).ResultsExpression of OSTα and OSTβ increased in PHH under conditions of hypoxia. Exposure of Huh7 cells or PHH to CDCA (50 μM) enhanced the effect of hypoxia on OSTα mRNA levels. In luciferase assays and EMSA, the inducing effect of low oxygen could be assigned to HIF-1α, which binds to hypoxia responsive elements (HRE) in the OSTα and OSTβ gene promoters. Site-directed mutagenesis of either the predicted HRE or the bile acid responsive FXR binding site abolished inducibility of the OSTα promoter, indicating that both elements need to be intact for induction by hypoxia and CDCA. In a rat model of chronic renal failure, the known increase in hepatic OSTα expression was associated with an increase in HIF-1α protein levels.ConclusionOSTα-OSTβ expression is induced by hypoxia. FXR and HIF-1α bind in close proximity to the OSTα gene promoter and produce synergistic effects on OSTα expression.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The organic solute transporters alpha and beta are induced by hypoxia in human hepatocytes

Schaffner

Mwinyi

Gai

et al. 2014

Liver International

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“…Moreover, decreased hepatic blood flow and increased portal pressure due to obstruction may cause hypoxia/ischemic damage liver paranchyma and bile duct. These features may increase cholestasis as reported by previous studies [34,35]. Matsumoto et al [34] suggested that the reduction in the number of fenestrae in the liver sinusoidal endothelial cells may lead to dysfunction of the liver microcirculation in the common bile ligated rats.…”

Section: Discussionmentioning

confidence: 71%

“…Matsumoto et al [34] suggested that the reduction in the number of fenestrae in the liver sinusoidal endothelial cells may lead to dysfunction of the liver microcirculation in the common bile ligated rats. Hypoxia/ischemia in the tissue may also directly induce an inflammatory response or promote expression vascular endothelial growth factor, which causes bile duct proliferation [35].…”

Section: Discussionmentioning

confidence: 99%

Utility of Diffusion-Weighted MRI to Detect Changes in Liver Diffusion in Benign and Malignant Distal Bile Duct Obstruction: The Influence of Choice of b-Values

et al. 2016

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“…25 We observed that UDCA-LPE prevented the loss of cIAP2 and Mcl-1 proteins known to be involved in intrinsic apoptosis. It is known that hypoxic condition in vivo can induce cholestasis 33 in part by upregulating bile acid transport genes. 34 An upregulation of cFLIP and the prevention of the loss of cIAP2 and Mcl-1 by UDCA-LPE would result in the resolution of apoptotic injury caused by hypoxia, and cholestasis at prolonger time.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins

Sellinger

Pathil

et al. 2014

Exp Biol Med (Maywood)

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An increase of toxic bile acids such as glycochenodeoxycholic acid occurs during warm ischemia reperfusion causing cholestasis and damage in hepatocytes and intrahepatic biliary epithelial cells. We aim to test antiapoptosis effects of ursodeoxycholyl lysophosphatidylethanolamide under cholestatic induction by glycochenodeoxycholic acid treatment of mouse hepatocytes and hypoxia induction by cobalt chloride treatment of intrahepatic biliary epithelial cancer Mz-ChA-1cell line. Such treatments caused marked increases in apoptosis as evidenced by activation of caspase 3, caspase 8 and poly (ADP-ribose) polymerase-1. Co-treatment with ursodeoxycholyl lysophosphatidylethanolamide significantly inhibited these increases. Interestingly, ursodeoxycholyl lysophosphatidylethanolamide was able to increase expression of antiapoptotic cellular FLICE-inhibitory protein in both cell types. Ursodeoxycholyl lysophosphatidylethanolamide also prevented the decreases of myeloid cell leukemia sequence-1 protein in both experimental systems, and this protection was due to ursodeoxycholyl lysophosphatidylethanolamide's ability to inhibit ubiquitination-mediated degradation of myeloid cell leukemia sequence-1, and to increase the phosphorylation of GSK-3b. In addition, ursodeoxycholyl lysophosphatidylethanolamide was able to prevent the decreased expression of another antiapoptotic cellular inhibitor of apoptosis 2 in cobalt chloride-treated Mz-ChA-1 cells. Hence, ursodeoxycholyl lysophosphatidylethanolamide mediated cytoprotection against apoptosis during toxic bile-acid and ischemic stresses by a mechanism involving accumulation of cellular FLICE-inhibitory protein, myeloid cell leukemia sequence-1 and cellular inhibitor of apoptosis 2 proteins. Ursodeoxycholyl lysophosphatidylethanolamide may thus be used as an agent to prevent hepatic ischemia reperfusion.

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Development of an experimental model of cholestasis induced by hypoxic/ischemic damage to the bile duct and liver tissues in infantile rats

Abstract: Reduced blood flow in the EBD during infancy induced BDPF and obstructive changes in the EBD, which may, along with immature PVP and inflammatory changes in the EBD, contribute to hypoxia/ischemia of the EBD.

Cited by 4 publications

References 35 publications

The organic solute transporters alpha and beta are induced by hypoxia in human hepatocytes

The organic solute transporters alpha and beta are induced by hypoxia in human hepatocytes

Utility of Diffusion-Weighted MRI to Detect Changes in Liver Diffusion in Benign and Malignant Distal Bile Duct Obstruction: The Influence of Choice of b-Values

Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins

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