Compensatory role of inducible annexin A2 for impaired biliary epithelial anion-exchange activity of inflammatory cholangiopathy

Kido, Osamu; Fukushima, Koji; Ueno, Yoshiyuki; Inoue, Jun; Jefferson, Douglas M.; Shimosegawa, Tooru

doi:10.1038/labinvest.2009.105

Cited by 5 publications

(7 citation statements)

References 60 publications

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“…Proteomic studies from H69 cells have revealed the expression of Annexin A2, a Ca 2 + ‐ and acidic phospholipid‐binding protein and a marker for normal human cholangiocytes . This proteomic study also identified the expression of AE2 and several markers of cholangiocytes in H69 cells . Furthermore, mRNA and protein levels of G‐protein‐coupled receptor 55 were found to be similar in H69, Mz‐ChA‐1, HuCCT cells and human intrahepatic biliary epithelial cells .…”

Section: Discussionmentioning

confidence: 65%

“…In addition, H69 cells contain Cl ‐ /HCO 3 ‐ anion exchanger 2 (AE2) mRNA and protein and were shown to have AE2‐mediated hydrocholeretic function similar to human cholangiocytes in 3D cultures . Proteomic studies from H69 cells have revealed the expression of Annexin A2, a Ca 2 + ‐ and acidic phospholipid‐binding protein and a marker for normal human cholangiocytes . This proteomic study also identified the expression of AE2 and several markers of cholangiocytes in H69 cells .…”

Section: Discussionmentioning

confidence: 81%

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Saturated free fatty acids induce cholangiocyte lipoapoptosis

et al. 2014

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Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration-dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment. Conclusion Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 81%

Saturated free fatty acids induce cholangiocyte lipoapoptosis

et al. 2014

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“…ANXA2 has many described functions but its role in the hepato-biliary system is not fully understood. It is expressed in many cells including hepatocytes, HSCs [15] and cholangiocytes [16]. ANXA2 is involved in the plasminogen/plasmin system with fibrinolytic effects promoting clot dissolution in alcoholic liver cirrhosis [15].…”

Section: Discussionmentioning

confidence: 99%

“…ANXA2 is involved in the plasminogen/plasmin system with fibrinolytic effects promoting clot dissolution in alcoholic liver cirrhosis [15]. In inflammatory cholangiopathy ANXA2 can mediate a compensatory effect for the impaired bicarbonate secretion of cholangiocytes through modulation of anion exchanger [16]. ANXA2 has been shown to be expressed as a vitamin D binding protein on hepatocytes and HSCs.…”

Section: Discussionmentioning

confidence: 99%

Multiplex transcriptional analysis of paraffin-embedded liver needle biopsy from patients with liver fibrosis

Staten

Welsh

Sidik

et al. 2012

Fibrogenesis Tissue Repair

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BackgroundThe possibility of extracting RNA and measuring RNA expression from paraffin sections can allow extensive investigations on stored paraffin samples obtained from diseased livers and could help with studies of the natural history of liver fibrosis and inflammation, and in particular, correlate basic mechanisms to clinical outcomes.ResultsTo address this issue, a pilot study of multiplex gene expression using branched-chain DNA technology was conducted to directly measure mRNA expression in formalin-fixed paraffin-embedded needle biopsy samples of human liver. Twenty-five genes were selected for evaluation based on evidence obtained from human fibrotic liver, a rat BDL model and in vitro cultures of immortalized human hepatic stellate cells. The expression levels of these 25 genes were then correlated with liver fibrosis and inflammation activity scores. Statistical analysis revealed that three genes (COL3A1, KRT18, and TUBB) could separate fibrotic from non-fibrotic samples and that the expression of ten genes (ANXA2, TIMP1, CTGF, COL4A1, KRT18, COL1A1, COL3A1, ACTA2, TGFB1, LOXL2) were positively correlated with the level of liver inflammation activity.ConclusionThis is the first report describing this multiplex technique for liver fibrosis and has provided the proof of concept of the suitability of RNA extracted from paraffin sections for investigating the modulation of a panel of proinflammatory and profibrogenic genes. This pilot study suggests that this technique will allow extensive investigations on paraffin samples from diseased livers and possibly from any other tissue. Using identical or other genes, this multiplex expression technique could be applied to samples obtained from extensive patient cohorts with stored paraffin samples in order to correlate gene expression with valuable clinically relevant information. This method could be used to provide a better understanding of the mechanisms of liver fibrosis and inflammation, its progression, and help development of new therapeutic approaches for this indication.

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“…These studies about the understanding of the heterogeneity of cholangiocytes will contribute to answering the key question regarding the selective destruction of bile ducts seen in PBC. Recently, we have applied 2-dimension gel electrophoresis to perform proteomics study (Kido et al 2009). With this sophisticated technique, we found that the expression of annexin A2 was increased in cholangiocytes when exposed to inflammatory cytokines.…”

Section: Primary Biliary Cirrhosis (Pbc)mentioning

confidence: 99%

The Current Endeavors to Understand the Pathogenesis of Intractable Liver Diseases

Ueno

2012

Tohoku J. Exp. Med.

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The death due to liver diseases accounts for more the 35,000 cases every year in Japan for decades. Among these liver diseases, the Ministry of Health, Labor, and Welfare of Japan has named both fulminant hepatitis and primary biliary cirrhosis (PBC) as intractable liver diseases, since the precise mechanism of these diseases are unclear. Accordingly, there are no effective medical treatments other than liver transplantation toward these diseases. However, still the number of the liver transplantation performed in Japan is small. Thus, we have focused on the pathogenesis of these two intractable conditions. The fulminant hepatitis is a distinct form of acute hepatitis, and hepatitis B virus infection accounts for 20~30% of this lethal condition. Only tiny proportions of patients with acute HBV infection develop fulminant hepatitis (less than 10%). It has been widely believed both viral and host factors contribute for fulminant hepatitis, although still unknown factors are expected to be involved. On the other hand, PBC is a chronic progressive cholestatic liver disease. Clinical features of PBC include female predominance (80 to 90%), the presence of antimitochondrial antibody (up to 95%), and elevated serum levels of immunoglobulin M. Eventually, patients with PBC will develop liver failure due to biliary cirrhosis in spite of medical interventions. Immune-mediated processes are believed to be responsible for the pathogenesis, although the precise mechanism is yet to be determined. In this review article, our endeavors to understand the mechanism of these intractable liver diseases are discussed.

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Compensatory role of inducible annexin A2 for impaired biliary epithelial anion-exchange activity of inflammatory cholangiopathy

Cited by 5 publications

References 60 publications

Saturated free fatty acids induce cholangiocyte lipoapoptosis

Saturated free fatty acids induce cholangiocyte lipoapoptosis

Multiplex transcriptional analysis of paraffin-embedded liver needle biopsy from patients with liver fibrosis

The Current Endeavors to Understand the Pathogenesis of Intractable Liver Diseases

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