Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis by both Fas-dependent and -independent mechanisms. However, the Fas-independent apoptosis also appears to be death receptor-mediated. Because death receptor-mediated apoptosis in hepatocytes requires proapoptotic Bcl-2 BH3 domain only protein Bid, we postulated that Fas-independent but death receptor-mediated bile acid cytotoxicity would be Bid-dependent. We used Fas-deficient lymphoproliferative (lpr) mouse hepatocytes for these studies, and inhibited Bid expression using an antisense approach. Glychochenodeoxycholate (GCDC) was used to induce apoptosis. Bid cleavage and translocation to mitochondria was observed in GCDC-treated cells as assessed by immunoblot analysis and confocal imaging of Bid-green fluorescent protein, respectively. Bid translocation to mitochondria was associated with cytochrome c release. A Bid antisense 2'-MOE modified oligonucleotide inhibited Bid expression in hepatocytes and markedly attenuated hepatocytes apoptosis by GCDC. Treatment of lpr mice with Bid antisense also ameliorated liver injury following bile duct ligation of the mice, a model of extrahepatic cholestasis. These results suggest that bile acid cytotoxicity is Bid-dependent despite the absence of Fas. Bid antisense therapy is a promising approach for the treatment of cholestatic liver injury.
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PMID:Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. 1171 70

It is well known that estrogen (E) modulates the processes of liver growth and regeneration. However, while estrogen receptors (Er) have been detected in hepatocytes, little is known on the occurrence of Er in cholangiocytes and the role of E on the physiopathology of the biliary epithelium. The purpose of this study was to investigate the occurrence of Er and their alpha or beta subtypes in cholangiocytes of normal and Bile Duct Ligated (BDL) rats and to evaluate the role and mechanisms of E in the modulation of cholangiocyte proliferation. In this study normal and BDL rats (utilized as experimental model of cholestasis) were used. Er alpha and beta subtypes, CK-19, PCNA and Fas were analysed by immunohistochemistry. The antiestrogens tamoxifen or ICI 182,780 were administered in the BDL group and the effects on cholangiocyte proliferation (bile duct mass) and apoptotic phenomenon (Tunel and Fas expression) were evaluated. Our results demonstrated that cholangiocytes express both Er-alpha and Er-beta subtypes, while hepatocytes only express Er-alpha. The increased percentage of cholangiocytes during BDL-induced proliferation was correlated with Er and PCNA expression and with enlarged Bile Duct Mass (BDM). Treatment of BDL rats with antiestrogens induced: i) inhibition of cholangiocyte proliferadon as indicated by the decreased BDM and PCNA expression; ii) over-expression of Fas antigen in cholangiocytes and induction of apoptosis (TUNEL) and iii) inhibition of cholangiocyte secretory activities. In condusion, our findings demonstrate that cholangiocytes express Er which are up-regulated during cholangiocyte proliferation. Inhibition of Er with antiestrogens blocks cholangiocyte proliferation and triggers apoptosis of Fas+ cholangiocytes suggesting a crucial role of estrogens in modulating cholangiocyte proliferation during bile duct obstruction.
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PMID:Immunohistochemical features of bile duct epithelial cells in normal and experimental liver conditions. 1172 79

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potential chemotherapeutic agent for cancer, is not thought to be hepatotoxic. We have recently demonstrated, however, that bile acids increase TRAIL-R2/DR5 expression in a human liver cell line and render these cells susceptible to TRAIL-mediated apoptosis. These data suggest TRAIL may be hepatotoxic in cholestasis. The aim of this study was to directly assess TRAIL hepatotoxicity in bile duct-ligated mice, a model of extrahepatic cholestasis. Bile duct-ligated mice (3 days) were used for these studies. TRAIL-R2/DR5 expression was assessed by real-time and immunoblot analysis. The TRAIL death-inducing signaling complex (DISC) was evaluated by immunoprecipitation and immunoblot techniques. Bile duct ligation increased both liver TRAIL-R2/DR5 mRNA and protein expression (>10-fold). Following TRAIL administration (60 microg/mouse, i.v.) to bile duct ligation (BDL) mice, terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive hepatocytes, liver tissue caspase 3-like activity, and serum alanine aminotransferase values increased significantly compared with vehicle-treated BDL mice. The effect of TRAIL on the liver was direct, as the TRAIL DISC (Fas-associated death domain and procaspase 8 protein) was detected in liver tissue. TRAIL-mediated hepatocyte apoptosis in bile duct-ligated mice was associated with significant hepatotoxicity, as assessed by histopathology, although there was no animal mortality. In conclusion, these data define conditions under which TRAIL is hepatotoxic.
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PMID:Cholestasis increases tumor necrosis factor-related apoptotis-inducing ligand (TRAIL)-R2/DR5 expression and sensitizes the liver to TRAIL-mediated cytotoxicity. 1238 24

Toxic bile acids facilitate Fas and tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) death-receptor oligomerization and activation. Bile acid modulation of death-receptor signaling is multifactorial and includes trafficking of Fas to the cell surface, enhancing TRAIL-R2/DR5 expression, and suppression of function of cFLIP, an antiapoptotic protein modulating death-receptor function. Because bile acid-associated death receptor-mediated apoptosis is a common mechanism for cholestatic hepatocyte injury, inhibition of death receptors and their cascades may prove useful in attenuating liver injury during cholestasis.
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PMID:Bile acid regulation of hepatic physiology: IV. Bile acids and death receptors. 1268 8

The goals of the current study are to examine the extent and mechanisms of apoptosis in cholestatic liver injury and to explore the role of the transcription factor nuclear factor-kappa B (NF-kappaB) in protection against bile acid-induced apoptosis. Cholestatic liver injury was induced by bile duct ligation in Wistar rats. Furthermore, primary cultures of rat hepatocytes were exposed to glycochenodeoxycholic acid (GCDCA), tauroursodeoxycholic acid, taurochenodeoxycholic acid, and to cytokines. Apoptosis was determined by TUNEL staining, active caspase-3 staining, and by activation of caspase-8, caspase-9, and caspase-3. Limited hepatocyte apoptosis and increased expression of NF-kappaB-regulated anti-apoptotic genes A1 and cIAP2 were detected in cholestatic rat liver specimens. Bcl-2 expression was restricted to bile duct epithelium. In contrast to taurochenodeoxycholic acid and tauroursodeoxycholic acid, GCDCA induced apoptosis in a Fas-associated protein with death domain-independent pathway in hepatocytes. Although bile acids do not activate NF-kappaB, NF-kappaB activation by cytokines (induced during cholestasis) protected against GCDCA-induced apoptosis in vitroby upregulating A1 and cIAP2. GCDCA induces apoptosis in a mitochondria-controlled pathway in which caspase-8 is activated in a Fas-associated protein with death domain-independent manner. However, bile acid-induced apoptosis in cholestasis is limited. This could be explained by cytokine-induced activation of NF-kappaB-regulated antiapoptosis genes like A1 and cIAP2.
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PMID:What doesn't kill you makes you stronger: how hepatocytes survive prolonged cholestasis. 1287 10

Extrahepatic cholestasis often evokes liver injury with hepatocyte apoptosis, aberrant cytokine production, and-most importantly-postoperative septic complications. To clarify the involvement of aberrant cytokine production and hepatocyte apoptosis in impaired resistance to bacterial infection in obstructive cholestasis, C57BL/6 mice or Fas-mutated lpr mice were inoculated intraperitoneally with 10(7) colony-forming units of Escherichia coli 5 days after bile duct ligation (BDL) or sham celiotomy. Cytokine levels in sera, liver, and immune cells were assessed via enzyme-linked immunosorbent assay or real-time reverse-transcriptase polymerase chain reaction. BDL mice showed delayed clearance of E. coli in peritoneal cavity, liver, and spleen. Significantly higher levels of serum interleukin (IL) 10 with lower levels of IL-12p40 were observed in BDL mice following E. coli infection. Interferon gamma production from liver lymphocytes in BDL mice was not increased after E. coli infection either at the transcriptional or protein level. Kupffer cells from BDL mice produced low levels of IL-12p40 and high levels of IL-10 in vitro in response to lipopolysaccharide derived from E. coli. In vivo administration of anti-IL-10 monoclonal antibody ameliorated the course of E. coli infection in BDL mice. Furthermore, BDL-lpr mice did not exhibit impairment in E. coli killing in association with little hepatic injury and a small amount of IL-10 production. In conclusion, increased IL-10 and reciprocally suppressed IL-12 production by Kupffer cells are responsible for deteriorated resistance to bacterial infection in BDL mice. Fas-mediated hepatocyte apoptosis in cholestasis may be involved in the predominant IL-10 production by Kupffer cells.
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PMID:Kupffer cell-derived interleukin 10 is responsible for impaired bacterial clearance in bile duct-ligated mice. 1536 46

Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
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PMID:Apoptosis and necrosis in the liver: a tale of two deaths? 1644 72

Apoptosis or programmed cell death occurs in the liver as in other organs. In the normal state it is not a frequent mode of hepatic cell destruction. Morphological and biochemical characteristics of liver cell apoptosis do not differ from what is observed in other cells. The Fas receptor pathway, a frequent hepatic apoptotic pathway among various others, involves intra-cellular signals amplified by mitochondria. Although hepatic apoptosis may occur by following several others pathways, Fas, which is abundantly expressed in the plasma membrane of hepatocytes, is very often involved in hepatocyte demise during B or C viral hepatitis irrespective of their clinical form, alcoholic hepatitis, cholestasis due to accumulation of hepatic biliary salts, or certain types of drug-induced hepatitis. Fas is also probably responsible for the death of biliary cells in primary biliary cirrhosis. In contrast one of the causes of resistance to apoptosis of hepatic cancerous cells could be related to an alteration of the Fas receptor. This is why much experimental work is presently performed to achieve inhibition of the Fas receptor either at the mRNA level or at the level of Fas-inductible proteolytic enzymes called caspases. One perspective is a specific treatment of apoptosis as an adjuvant treatment of liver diseases.
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PMID:[Liver apoptosis]. 1673 75

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. Our aim was to clarify the protective pathway in death receptor-mediated hepatocyte apoptosis and the significance of apoptosis in liver injury. In vitro: AdIkappaBsr plus tumor necrosis factor (TNF)-alpha/Jo2 rapidly induced apoptosis in mouse hepatocyte, whereas TNF-alpha/Jo2 alone produced little cytotoxicity. The combination of the mitochondrial permeability transition (MPT) inhibitors, cyclosporine A and trifluoperazine, protected AdIkappaBsr-infected hepatocytes from TNF-alpha- but not Fas-mediated apoptosis. The TNF-alpha and Jo2 induced iNOS through NF-kappaB. Nitric oxide donor (S-nitroso-N-acetylpenicillamine) inhibited Bid cleavage, the MPT, and caspase activation and reduced TNF-alpha- and Fas-mediated cell killing. Inhibition of PI3K by LY294,002 and a dominant-negative Akt, which attenuated NF-kappaB activation by TNF-alpha or Jo2, sensitized hepatocytes to TNF- or Jo2. In vivo: apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion injury. Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic ischemia/reperfusion injury in the rat, through Bad not NF-kappaB. Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis. Hepatocyte apoptosis has a major role in hepatic injury by bile duct ligation. At least, early hepatic injury by bile duct ligation involved Fas-mediated and Bcl-xL insensitive apoptotic pathway. In conclusion, the role of apoptosis in various liver diseases may suggest possible treatments.
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PMID:Tumor necrosis factor signaling in hepatocyte apoptosis. 1756 63

Liver injury in intercellular adhesion molecule 1 knockout (ICAM(-/-)) and Fas receptor-deficient (lpr) mice is markedly reduced after common bile duct ligation (CBDL) due to significantly reduced inflammation and oxidative stress. Liver injury in CBDL rodents is counteracted by adaptive hepatobiliary transporter induction. Since hepatobiliary transporter expression in obstructive cholestasis may be regulated not only by accumulating bile acids but also by inflammatory mediators and oxidative stress, we hypothesized that differences in the inflammatory response may affect hepatobiliary transporter expression in CBDL, which would contribute to reduced liver injury. Therefore, expression of major hepatobiliary transporters (Ntcp, Bsep, Mrp2-4, Ost alpha/beta) was determined by Taqman RT-PCR and Western blotting in sham-operated animals and 3 days after CBDL in wild-type, ICAM(-/-) and lpr mice of the endotoxin-sensitive C57BL/6 and the endotoxin-resistant C3H/HeJ strains. CBDL resulted in a significant decrease of Ntcp in all genotypes. Canalicular transporters Bsep and Mrp2 were repressed only in the endotoxin-sensitive strain regardless of the genotype. Mrp3 was moderately induced in ICAM(-/-), lpr, and endotoxin-resistant mice, whereas Mrp4 was only induced in the endotoxin-resistant strain. Ost beta was massively induced in all CBDL mice, whereas Ost alpha was reduced. In conclusion, markedly reduced inflammation and oxidative stress in CBDL ICAM(-/-) and lpr mice does not profoundly affect hepatobiliary transporter expression. Therefore, transporter expression does not account for reduced liver injury in ICAM(-/-) and lpr mice. Induction of the adaptive transporter response after CBDL is independent of the degree of the inflammatory response. Rather, retention of biliary constituents may determine transporter expression in CBDL.
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PMID:Hepatobiliary transporter expression in intercellular adhesion molecule 1 knockout and Fas receptor-deficient mice after common bile duct ligation is independent of the degree of inflammation and oxidative stress. 1757 7


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