Yasuni Nakanuma

Shizuoka Cancer Center, Sizuoka, Shizuoka, Japan

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Publications (876)3161.23 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We thank Dr. Tapan and Sertoglu for their interest in our study and their comments. In the letter to the Editor, they recommend to measure fatty acid composition after excluding patients with type 2 diabetes mellitus (T2DM) because the activity of the desaturase enzymes regulating especially polyunsaturated fatty acids can be affected by T2DM and correlates with the level of fasting plasma glucose and insulin resistance [1]. In our study, HbA1c levels are 7.1±0.2% and 7.1±0.3% for simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) groups, respectively, and the patients with T2DM are included in both SS and NASH groups. The number of patients with T2DM was 42/63 (66.7%) and 29/40 (72.5%) for SS and NASH groups, respectively, and there was no statistically significant difference in the rate of T2DM between SS and NASH groups. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 12/2014; · 3.87 Impact Factor
  • Yasuni Nakanuma, Motoko Sasaski, Kenichi Harada
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    ABSTRACT: Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC, and deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology. 11/2014;
  • Yuko Kakuda, Kenichi Harada, Yasuni Nakanuma
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    ABSTRACT: The canals of Hering (CoH), which are the most peripherally located bile drainage pathway, are considered a niche of hepatic progenitor cells. Recently, CoH loss has been described as an early feature of primary biliary cirrhosis (PBC). We investigated the correlation between CoH loss and the histopathological variables of PBC. Liver biopsy specimens from 62 PBC patients (M:F=8:54, age=58±12 years) were evaluated prior to ursodeoxycholic acid treatment. Liver biopsies of patients with normal liver (n=11), chronic viral hepatitis (n=36) and non-alcoholic fatty liver disease (n=13) were used as controls. The number of CoH per definite area of hepatic parenchyma (c to p ratio) was calculated in individual cases. We compared the c to p ratios of PBC patients with that of controls and analysed the correlations with histological variables and clinical features. The c to p ratios in PBC patients with mild and extensive fibrosis were lower than those in controls with each degree of fibrosis. The c to p ratios were negatively correlated with stage, fibrosis, bile duct loss, orcein-positive granule deposition and hepatitis activities in PBC (p<0.01) and with alkaline phosphatase and total bilirubin levels at liver biopsies (p<0.05). The number of CoH was low in early stages and further decreased with stage progression in PBC. CoH loss, reflecting a reduced supply of progenitor cells to the biliary tree, may be involved in the histological progression of PBC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of clinical pathology. 11/2014;
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    ABSTRACT: Similar to the pancreatic carcinoma sequence model, cholangiocarcinoma reportedly follows a stepwise carcinogenesis process via the precursor lesion biliary intraepithelial neoplasia (BilIN). Given that autophagy plays an important role in the occurrence and development of carcinomas, we examined the involvement of autophagy in multistep cholangiocarcinogenesis. Thirty-six patients with hepatolithiasis associated with BilIN and/or cholangiocarcinoma, 7 with intrahepatic cholangiocarcinoma, 8 with intraductal papillary neoplasm of the bile duct (IPNB) and 6 with control livers were surveyed. Their lesions were categorized as follows: invasive carcinoma (n = 16), IPNB (n = 8), BIlN-3 (n = 16), BilIN-1/2 (n = 40), non-neoplastic large bile duct (LBD) (n = 55) and peribiliary gland (PBG) (n = 55). We examined the immunohistochemical expression of autophagy-related proteins, microtubule-associated proteins light chain 3β (LC3), beclin-1 and p62/sequestosome-1 (p62), as well as tumor suppressor gene product p53. The extent of expression was semiquantitatively assessed. The status of KRAS mutations at codons 12 and 13 was examined in selected cases of BilIN-1/2. The expression of LC3 (cytoplasmic), beclin-1 (cytoplasmic) and p62 (cytoplasmic and nuclear) was significantly higher in BilIN-1/2, BilIN-3, IPNB and invasive carcinoma than in LBD and PBG (p < 0.01). KRAS mutation was detected in 6 of 15 BilIN-1/2 (40%) and there was no correlation between the status of KRAS mutation and the expression of autophagy-related proteins. In conclusion, this study is the first to disclose that the expression of autophagy-related proteins, LC3, beclin-1 and p62, was increased at an early stage of multistep cholangiocarcinogenesis in hepatolithiasis. Autophagy, probably deregulated autophagy, may be related to the occurrence and development of cholangiocarcinoma.
    Human pathology 10/2014; · 3.03 Impact Factor
  • Motoko Sasaki, Yasuni Nakanuma
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    ABSTRACT: A subgroup of intrahepatic cholangiocarcinoma and combined hepatocellular- cholangiocarcinoma contain a component of cholangiolocellular carcinoma, which is composed of small bile ductular cells. Ductular reaction, a reactive lesion at the portal tract interface comprising increased bile ductules, is frequently seen in chronic advanced liver diseases. Bile duct adenoma, a benign tumor/tumorous lesion is also composed of bile ductular cells. Differential diagnosis among these bile ductular tumors/lesions is sometimes difficult. Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile ductular tumors/lesions. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, while it was not observed in bile duct adenomas or ductular reactions. In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas. A borderline between cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a. In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile ductular tumors/lesions.
    Histology and histopathology 10/2014; · 2.28 Impact Factor
  • Kenichi Harada, Yasuni Nakanuma
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    ABSTRACT: IgG4-related diseases including IgG4-related sclerosing cholangitis are characterized by the increased level of serum IgG4 and the marked infiltration of IgG4+ plasma cells in affected organs. However, several cases of extrahepatic biliary cancers often accompany the significant infiltration of IgG4+ cells. IL-10 is an important regulatory cytokine associated with the differentiation of IgG4-producing plasma cells and the IgG4 reaction in biliary cancers shows a negative correlation with CD8+ cytotoxic T cells, suggesting that the IgG4 reaction in biliary cancers is associated with the evasion of the tumor-related immune surveillance. Moreover, cancer cells could play a role of regulatory functions by themselves directly and indirectly via a production of IL-10. To clarify the association with IgG4 reaction in the carcinogenesis of cholangiocarcinoma, we examined the IgG4 reaction in its precursor lesion biliary intraepithelial neoplasia (BilIN). Consequently, although a few or none IgG4+ cells were found in BilIN1 and BilIN2 lesions, several or many positive cells were scattered around the large bile ducts showing BilIN3, irrespective of the degree of periductal inflammation. These findings suggest that IgG4 reaction reflects the regulatory cytokine milieu associated with the extrahepatic biliary cancers and also its carcinogenesis, especially the development from BilIN2 to BilIN3.
    Pathology 10/2014; 46 Suppl 2:S23. · 2.66 Impact Factor
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    ABSTRACT: AimsWe characterized serum amyloid A (SAA)-positive hepatocellular neoplasm/nodules arising in alcoholic cirrhosis, which is detected as a hypervascular hepatocellular nodules resembling hepatocellular carcinoma on imaging.Methods and ResultsFifty-three hepatocellular nodules were examined using immunostaining for SAA, glutamine synthetase and glypican-3 in 23 patients (4 women and 19 men) with alcoholic cirrhosis. Sixteen nodules were examined on the magnetic resonance imaging with EOB enhancement (EOB-MRI). Somatic mutations on IL6ST, GNAS and STAT3 were examined in 19 nodules. Thirty-six nodules in 18 patients were diagnosed as SAA-positive hepatocellular neoplasm/nodules and the remaining seventeen nodules in 8 patients were SAA-negative focal nodular hyperplasia (FNH)-like nodules. SAA-positive hepatocellular neoplasms/nodules showed significantly more extensive sinusoidal dilatation, inflammatory reaction, abnormal thick arteries and cellular atypia than FNH-like nodules (p<0.05). Eight SAA-positive hepatocellular neoplasms/nodules (67%) showed slight hypointensity in the hepatobiliary phase on the EOB-MRI, whereas all 4 FNH-like nodules showed iso-intensity (p<0.05). STAT3 mutations were detected in 2 of 17 SAA-positive hepatocellular neoplasms/nodules.Conclusions This study disclosed that about two thirds of hypervascular hepatocellular nodules arising in alcoholic cirrhosis were SAA-positive hepatocellular neoplasms/nodules which show different finings on the EOB-MRI. STAT3 mutations were detected in 11.8% of SAA-positive hepatocellular neoplasms/nodules, supporting neoplastic nature.This article is protected by copyright. All rights reserved.
    Histopathology 10/2014; · 2.86 Impact Factor
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    ABSTRACT: Bezafibrate is reported to have biochemical efficacy for patients with primary biliary cirrhosis (PBC) refractory to ursodeoxycholic acid (UDCA), yet the long-term effect is still unknown. In Japan, nationwide surveys of PBC have been performed since 1980. In the current study, we retrospectively examined whether response to bezafibrate treatment is associated with the long-term outcomes using this large-scale database.
    Journal of gastroenterology. 09/2014;
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and lipid metabolism. Recent studies have suggested that the quality of fat accumulated in the liver is associated with the development of nonalcoholic steatohepatitis (NASH). In this study, we investigated the fatty acid composition in liver tissue and its association with the pathology in NAFLD patients.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014; · 3.87 Impact Factor
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    ABSTRACT: Background & aimsThe aim of the present study is to evaluate the factors influencing biochemical response to treatment and the value of biochemical response for predicting long-term outcomes in Japanese patients with PBC.Patients and Methods Biochemical response to ursodeoxycholic acid (UDCA) or UDCA plus bezafibrate was defined as good (≤ULN), fair (≤1.5 x ULN), or poor (>1.5 x ULN) at 2 years after initiation of UDCA treatment. Associations between various factors (including age, sex, autoantibody status, and histological variables at baseline), biochemical response to treatment, and long-term outcomes were evaluated in 164 Japanese PBC patients.ResultsAnti-gp210 positivity and a higher bile duct loss score were significant risk factors for worse ALP response (OR, 2.78 and 1.85, respectively). Age, anti-gp210 positivity, and anti-centromere positivity were significant risk factors for worse ALT response (OR, 1.05, 4.0, and 2.77, respectively). Anti-gp210 positivity and a higher hepatitis score were significant risk factors for worse IgM response (OR, 2.10 and 2.06, respectively). Worse ALP and IgM response were significant risk factors for progression to late-stage disease without jaundice (OR, 2.27 and 2.32, respectively). Worse ALT response was a significant risk factor for progression to late-stage disease with persistent jaundice (OR, 11.11).Conclusions Biochemical response to treatment at 2 years, which is influenced by autoantibody status and histological variables at baseline, can predict long-term outcomes in Japanese patients with PBC.
    Hepatology Research 09/2014; · 2.07 Impact Factor
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    ABSTRACT: Background Cholangiocarcinoma has been reported in workers exposed to chlorinated organic solvents and has consequently been classified as an occupational disease (occupational cholangiocarcinoma) by the Japanese Ministry of Health, Labour and Welfare. This study aimed to identify the characteristics of nine workers newly diagnosed with occupational cholangiocarcinoma.Methods This study was a retrospective study conducted in 13 hospitals and three universities. Clinicopathological findings of nine occupational cholangiocarcinoma patients from seven printing companies in Japan were investigated and compared with 17 cholangiocarcinoma patients clustered in a single printing company in Osaka.ResultsPatient age at diagnosis was 31–57 years. Patients were exposed to 1,2-dichloropropane and/or dichloromethane. Serum γ-glutamyl transpeptidase activity was elevated in all patients. Regional dilatation of the intrahepatic bile ducts without tumor-induced obstruction was observed in two patients. Four patients developed intrahepatic cholangiocarcinoma and five developed hilar cholangiocarcinoma. Biliary intraepithelial neoplasia and/or intraductal papillary neoplasm of the bile duct was observed in four patients with available operative or autopsy specimens.Conclusions Most of these patients with occupational cholangiocarcinoma exhibited typical findings, including high serum γ-glutamyl transpeptidase activity, regional dilatation of the bile ducts, and precancerous lesions, similar to findings previously reported in 17 occupational cholangiocarcinoma patients in Osaka.
    Journal of Hepato-Biliary-Pancreatic Sciences. 09/2014;
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    ABSTRACT: A 60-year-old woman with neurofibromatosis type 1 presented to our hospital with melena. She reported a 1-year history of treatment with nilotinib hydrochloride hydrate for chronic myelogenous leukemia. Contrast-enhanced abdominal computed tomography revealed multiple intestinal tumors that were subsequently diagnosed as gastrointestinal stromal tumors (GIST) using single-balloon enteroscopy. Although the tumors showed no significant change over 1 year, partial jejunal resection was performed to confirm the diagnosis. Immunohistochemically, the tumors were GIST.
    08/2014; 111(8):1579-86.
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    ABSTRACT: Immunoglobulin G4 (IgG4)-related aortitis/periaortitis and periarteritis are vascular manifestations of IgG4-related disease. In this disease, the affected aneurysmal lesion has been suspected to be at risk of rupture. This study aimed to clarify the clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis.
    Arthritis research & therapy. 07/2014; 16(4):R156.
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    ABSTRACT: Objectives: A cholangiocarcinoma outbreak among workers of an offset color proof-printing department in a printing company was recently reported. It is important to understand the clinical course leading to occupational cholangiocarcinoma development for investigation of the carcinogenesis process and for surveillance and early detection. We evaluated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma. Methods: We investigated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma in 2 patients because the data were available. Results: The clinical courses observed in the 2 participating patients showed persistent elevation of serum γ-glutamyl transpeptidase levels with or without elevated serum levels of alanine aminotransferase and/or aspartate aminotransferase before cholangiocarcinoma detection. Dilatation of the bile ducts without tumor-induced stenosis was observed several years before cholangiocarcinoma detection and progressed gradually in both patients. The serum concentration of carbohydrate 19-9 also increased prior to cholangiocarcinoma detection in both patients. Eventually, observation of stenosis of the bile duct and a space-occupying lesion strongly suggested cholangiocarcinoma. Pathological examination of the resected specimens showed chronic bile duct injury and neoplastic lesions, such as "biliary intraepithelial neoplasia" and "intraductal papillary neoplasm of the bile duct" in various sites of the bile ducts, particularly in the dilated bile ducts. Conclusion: The changes in laboratory test results and diagnostic imaging might be related to the development of cholangiocarcinoma. It is important to monitor diagnostic imaging presentation and laboratory test results in workers with extended exposure to organic solvents.
    Journal of Occupational Health 06/2014; · 1.63 Impact Factor
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    ABSTRACT: We describe a 74-year-old Japanese man with systemic fibroinflammatory conditions closely resembling those of immunoglobulin G4-related disease (IgG4-RD). Radiology and histology showed characteristics of IgG4-related tubulointerstitial nephritis, despite normal serum IgG4 value and scanty IgG4-positive plasma cell infiltration in each organ. This case suggests that a condition closely mimicking IgG4-RD may develop without IgG4-positive plasma cells and those exceptional cases should also be taken into account in the differential diagnosis of IgG4-RD.
    Modern rheumatology / the Japan Rheumatism Association. 06/2014;
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    ABSTRACT: A 39-year-old male with elevated serum transferases consulted our hospital in September 2010. Since 1999, he had worked at a printing company using organic solvents. Cholangiography revealed stenosis of the left hepatic duct with peripheral dilation, stricture of the right hepatic duct, and irregularity of the extrahepatic bile duct. As a preoperative diagnosis of sclerosing cholangitis and cholangiocarcinoma was made, extended left hepatectomy with resection of the extrahepatic bile duct and anastomosis of the anterior and posterior branches of the bile duct and the jejunum (Roux-en Y reconstruction) were performed. A histological examination showed papillary carcinoma of the medial hepatic bile duct with intraductal growth, and biliary intraepithelial neoplasia-2/3 lesions from the medial hepatic bile duct to the right hepatic and the common bile ducts. Chronic cholangitis was shown around the tumors. Postoperatively, the patient was treated with adjuvant chemo-radiation, and he is doing well 30 months after the operation, without recurrence. Unknown causes, including exposure to organic solvents, might have induced chronic bile duct injury and contributed to the development of cholangiocarcinoma.
    Osaka city medical journal. 06/2014; 60(1):39-44.
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    ABSTRACT: The aims of the present study are to clarify the changes in clinicopathologic features, diagnosis and treatment for hepatolithiasis, and propose an appropriate management strategy in Japan. The research group conducted nationwide surveys seven times in the past over a period of 40 years. Furthermore, a cohort was followed up in 2010. We analyzed the clinical features, diagnosis tools, treatment procedures, outcomes, and predictive factors for cholangiocarcinoma. Surgery was the primary method for hepatolithiasis up to 1998, and the frequency of its use has decreased since then. In 2011, 66.7% of hepatolithiasis patients were treated using nonsurgical approaches. In addition, endoscopic retrograde cholangiography (ERC) with stone extraction was the most frequently performed procedure (22.7%). However, the incidences of residual stone and recurrent stone after ERC with stone extraction were higher than those after percutaneous transhepatic cholangioscopic lithotomy and surgery. Bile duct stricture and dilatation during follow up were significant risk factors for stone recurrences. In the cohort study, stone removal only and age >65 years were significant factors for the development of cholangiocarcinoma. In patients without a history of cholangioenterostomy, left-lobe-type stones were a risk factor, and hepatectomy reduced the risk of the development of cholangiocarcinoma significantly. Nonsurgical treatment may be performed as the first-line treatment for hepatolithiasis. Surgery should be performed on patients who were treated incompletely after nonsurgical treatment. However, hepatectomy may be recommended for patients with left-lobe-type stones and without a history of cholangioenterostomy.
    Journal of hepato-biliary-pancreatic sciences. 05/2014;
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    ABSTRACT: To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgG-equal, and IgG-predominant types, with the latter sharing several features with AIH. These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.
    World Journal of Gastroenterology 04/2014; 20(13):3597-608. · 2.55 Impact Factor
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    ABSTRACT: BackgroundsCombined hepatocellular-cholangiocarcinoma (cHC-CC), a malignant liver tumor with poor prognosis, is composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and diverse components with intermediate features between HCC and CC, which correspond to hepatic progenitor cells.AimsAccording to the WHO classification 2010, we surveyed the prevalence and clinicopathological significance of each subtype with stem cell features (SC subtype; typical subtype [TS], intermediate cell subtype [INT] and cholangiolocellular type [CLC]) in cHC-CC and HCC.Methods Sixty-two patients with cHC-CC (19 women and 43 men) and 26 patients with HCC (all men) were examined. The prevalence of each component was histologically assessed with assistance of mucin and immunohistochemical stainings.ResultsSC subtypes were observed in all cHC-CCs in various amount and combination. The prevalence of each SC subtype in cHC-CC was as follows; TS, 10 (16.1%); INT, 53 (83.9%); and CLC, 44 (71.0%). The proportion of INT was significantly correlated to gender (female-dominant) (p<0.05), tumor size (p<0.05), histological grading of HCC (p<0.01) and inversely correlated to the degree of stromal fibrosis (p<0.05). The proportion of CLC was significantly correlated to the degree of fibrosis (p<0.01) and inflammation (p<0.01), and inversely correlated to tumor size (p<0.01) and histological grading of HCC (p<0.05). The proportion of TS was significantly inversely correlated to the degree of inflammation (p<0.01). Histological diversity score was significantly correlated to vascular invasion and the positivity for α-fetoprotein.Conclusion The proportion of each SC subtype was significantly associated with certain clinicopathological factors, suggesting different properties of each SC subtypes.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 04/2014; · 3.87 Impact Factor
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    ABSTRACT: Oestrogen has been speculated to play an important role in the pathogenesis of primary biliary cirrhosis (PBC), which mainly affects middle-aged and old-aged females because biliary epithelial cells (BECs) are known to express oestrogen receptors (ERs). Oestrogen-related receptors (ERRs) are constitutively active without oestrogen and competitively inhibit the ER-dependent effects of oestrogen. We clarified the effects of oestrogen and the significance of ERRs along with their association with the pathogenesis of cholangiopathy in PBC. We investigated the expression of ERs and ERRs and the apoptosis-related cell kinetics in BECs using cultured human BECs and human liver specimens. Although cultured human BECs and the interlobular bile ducts in the liver expressed ERβ, in cultured BECs, oestrogen treatment did not induce significant cell proliferation but increased the expression of a negative cell proliferation regulator (14-3-3σ protein). The cultured BECs constantly expressed ERRα and ERRγ, and oestrogen downregulated the ERRγ expression. Furthermore, the ERRγ expression was determined in the intrahepatic bile ducts and was stronger in the middle-aged and old-aged females, particularly those with PBC, than in the younger females. The ERRγ ligand activated a transcription factor, SP1, and enhanced the expression of the pro-apoptotic Bcl-2 family molecules and Bcl-2 inhibitor-induced apoptosis in cultured BECs. Although oestrogen downregulates the ERRγ expression, the increased ERRγ expression under oestrogen-deficient conditions increases the susceptibility to Bcl-2 family-mediated apoptosis in cultured human BECs of females, particularly those with PBC. Understanding the oestrogen-mediated cell kinetics is important for elucidating the pathogenesis of cholangiopathy in PBC.
    Journal of clinical pathology 03/2014; · 2.43 Impact Factor

Publication Stats

16k Citations
3,161.23 Total Impact Points

Institutions

  • 2014
    • Shizuoka Cancer Center
      Sizuoka, Shizuoka, Japan
  • 1987–2014
    • Kanazawa Medical University
      • • Department of Radiology
      • • Department of Gastroenterology
      • • Department of Pathology
      • • Department of Internal Medicine (III)
      Kanazawa, Ishikawa, Japan
  • 1979–2014
    • Kanazawa University
      • • Department of Gastroenterology
      • • Department of Disease Control and Homeostasis
      • • School of Medicine
      • • Department of Radiology
      • • Department of Internal Medicine
      Kanazawa, Ishikawa, Japan
  • 2013
    • North Internal Medicine
      Bartlett, Tennessee, United States
    • Tohoku University
      Japan
    • Osaka City University
      • Department of Hepato-Biliary-Pancreatic Surgery
      Ōsaka, Ōsaka, Japan
  • 2009–2013
    • King's College London
      • Department of Immunobiology
      Londinium, England, United Kingdom
  • 2012
    • Toyama University
      Kanazawa, Ishikawa, Japan
    • Tokyo Women's Medical University
      • Institute of Gastroenterology
      Edo, Tōkyō, Japan
    • University of Toyama
      • Graduate School of Medicine and Pharmaceutical Science for Education
      Toyama-shi, Toyama-ken, Japan
    • Nagoya City University
      Nagoya, Aichi, Japan
  • 2008–2012
    • Kyoto Prefectural University of Medicine
      • Graduate School of Medical Science
      Kioto, Kyōto, Japan
    • National Hospital Organization Sagamihara Hospital
      Sagamihara, Kanagawa, Japan
    • Kyushu University
      • Graduate School of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2011
    • Sungkyunkwan University
      • Department of Radiology
      Seoul, Seoul, South Korea
  • 2004–2011
    • Kyoto University
      • Department of Diagnostic Pathology
      Kyoto, Kyoto-fu, Japan
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 1988–2008
    • Ishikawa Prefectural Central Hospital
      Ishiza, Okinawa, Japan
  • 2006
    • National Cancer Center, Japan
      • Department of Diagnostic Radiology
      Edo, Tōkyō, Japan
  • 2003
    • State University of New York Downstate Medical Center
      • Department of Pathology
      Brooklyn, NY, United States
  • 1993–2002
    • University of California, Davis
      • Division of Rheumatology/Allergy/Clinical Immunology
      Davis, CA, United States
  • 1993–1999
    • University of California, San Francisco
      • Department of Pathology
      San Francisco, California, United States
  • 1988–1999
    • Nagai Internal Medicine Clinic
      Okayama, Okayama, Japan
  • 1997
    • Tottori University
      • Faculty of Medicine
      Tottori, Tottori-ken, Japan
  • 1986
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States