田中　裕滋 （タナカ　ユウジ）

コミュニケーション情報 byコメンテータガイド

• コメント

  酸化ストレス防御遺伝子を調節する転写因子Nrf2の脂質代謝と鉄代謝における役割について研究しています。 Nrf2を標的とし、食品由来の機能性成分による脂肪肝炎の予防に取り組んでいます。

研究者情報

学位

• 博士 (医学)（2002年03月）

ホームページURL

https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201401015358703769

J-Global ID

• 201401015358703769

研究キーワード

• TICE   胆汁酸代謝   脂質代謝   非アルコール性脂肪肝炎   Nrf2   ビリルビン代謝   

現在の研究分野（キーワード）

酸化ストレス防御遺伝子を調節する転写因子Nrf2の脂質代謝と鉄代謝における役割について研究しています。
Nrf2を標的とし、食品由来の機能性成分による脂肪肝炎の予防に取り組んでいます。

研究分野

• その他 / その他 / 病態検査学
• ライフサイエンス / 代謝、内分泌学
• ライフサイエンス / 消化器内科学
• 人文・社会 / 家政学、生活科学
• ライフサイエンス / 食品科学

経歴

• 2015年04月  近畿大学医学部附属病院Faculty of Medicine講師
• 2007年08月  近畿大学医学部附属病院Faculty of Medicine医学部講師
• 2007年01月  カンザス大学医療センター講師

学歴

•         - 2002年03月   三重大学   医学研究科   内科学
•         - 1994年03月   三重大学   医学部   医学科

所属学協会

• 日本感染症学会   米国肝臓学会   日本医学教育学会   日本糖尿病学会   日本栄養・食糧学会   日本消化器内視鏡学会   日本消化器病学会   日本肝臓学会   日本内科学会   日本臨床検査医学会   日本臨床検査専門医会   米国毒性学会   

研究活動情報

論文

• Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet.

  Toshinori Kamisako; Yuji Tanaka

  Journal of clinical biochemistry and nutrition 70 2 147 - 153 2022年03月 [査読有り]
   

  Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in the development of experimental steatohepatitis in rodents. In this study, to evaluate the effect of oltipraz on lipid and bile acid metabolism, wild-type and Nrf2-null mice were fed the standard diet (containing 4% soybean oil) with or without oltipraz. Based on these results, we examined the effect of oltipraz on the experimental steatohepatitis in high-fat diet (containing 4% soybean oil and 20% lard) fed Nrf2-null mice. Oltipraz induced hepatic mRNA expression of peroxisome proliferator-activated receptor α, carnitine palmityl transferase 1, and bile salt export pump by Nrf2 independent mechanisms. In Nrf2-null mice fed a high-fat diet for 12 weeks, moderate to severe inflammation and fibrosis were observed. Oral administration of oltipraz suppressed the degree of inflammation and fibrosis in Nrf2-null mouse liver fed a high-fat diet. These histopathological findings approximately corresponded to the data of mRNA expression of tumor necrosis factor α, monocyte chemoattractant protein-1, Timp-1, and collagen type 1α1. These results indicated that oltipraz administration ameliorated liver injury by Nrf2 independent manner in a model of steatohepatitis generated by Nrf2-null mice with high-fat diet.
• Regulation of the expression of cholesterol transporters by lipid-lowering drugs ezetimibe and pemafibrate in rat liver and intestine.

  Yuji Tanaka; Toshinori Kamisako

  Biochimica et biophysica acta. Molecular basis of disease 1867 11 166215 - 166215 2021年07月 [査読有り]
   

  Ezetimibe and pemafibrate are lipid-lowering drugs and promote reverse cholesterol transport. However, it is unknown whether cholesterol is mainly excreted by hepatobiliary excretion or by non-biliary transintestinal cholesterol efflux (TICE). We evaluated the effects of ezetimibe and pemafibrate on hepatic and intestinal cholesterol transporter regulation in Sham-operated rats, and examined the effects of these drugs on TICE in bile duct-ligated rats. Seven-week-old male Sprague-Dawley rats were treated as follows for two weeks: 1) Sham, Sham operation; 2) BDL, bile duct ligation; 3) E-Sham, Sham + ezetimibe; 4) E-BDL, BDL + ezetimibe; 5) P-Sham, Sham + pemafibrate; and 6) P-BDL, BDL + pemafibrate. Blood, liver, jejunum, and feces were collected 72 h post-surgery. Hepatic cholesterol levels were decreased in P-Sham and E-Sham, and were lower in E-BDL and P-BDL than in BDL. Fecal cholesterol levels increased in E-Sham and P-Sham compared with Sham, and were higher in E-BDL and P-BDL than in BDL. In liver, Abcg5 mRNA showed induction in E-Sham, Abcg5 and Abca1 mRNA were induced in P-Sham, Abcg5 mRNA was reduced in E-BDL, and Abca1 mRNA was increased in P-BDL. In jejunum, Abcg5 mRNA was induced in E-Sham. Abcg8 mRNA was induced in E-Sham and P-Sham. NPC1L1 mRNA showed reduced expression in P-Sham and P-BDL. SR-B1 mRNA was reduced in P-Sham, and the expression decreased in P-BDL. LDL receptor mRNA was induced in BDL and P-BDL. Ezetimibe and pemafibrate may promote TICE by increasing Abcg5/g8, while pemafibrate may inhibit intestinal cholesterol absorption by decreasing SR-B1 and NPC1L1.
• Ezetimibe markedly reduces hepatic triglycerides and cholesterol in rats fed on fish oil by increasing the expression of cholesterol efflux transporters.

  Yuji Tanaka; Takanori Ikeda; Hiroshi Ogawa; Toshinori Kamisako

  The Journal of pharmacology and experimental therapeutics 2020年05月 [査読有り]
   

  Besides diet therapy, hypolipidemic pharmacological therapy may be a crucial component of nonalcoholic fatty liver disease (NAFLD) treatment. Ezetimibe may be a promising drug for treatment of NAFLD. N-3 polyunsaturated fatty acids, which are abundant in fish oil, reduces serum and hepatic cholesterol and triglycerides in rodents. The aim of this study was to examine the combined effects of dietary fish oil and ezetimibe on lipid metabolism in rats. Seven-week old male SD rats were allocated to four different diets containing 1) 10% soybean oil (C), 2) 10% fish oil (F), 3) 10% soybean oil + 0.005% ezetimibe (E), and 4) 10% fish oil + 0.005% ezetimibe (F+E) for 4 weeks, when the liver, jejunum, blood, and fecal samples were collected. Compared to the C group, the F+E-diet decreased hepatic triglycerides and cholesterol 84% and 86%, but it did not increase fecal cholesterol. In liver, the expression of lipogenic enzymes were decreased in F+E diet, whereas β-oxidation related genes were not increased. Abcg5/g8 mRNA expression were increased 1380%/442% when ezetimibe was added to the F-diet. These gene expression changes are related to the decrease in hepatic lipids. In jejunum, Abcg5/g8 mRNA were increased 244%/841% when ezetimibe was added to the F-diet. Hepatic induction of Abcg5/8 rather than intestinal induction correlates with the marked decrease in liver cholesterol when ezetimibe was added to the F-diet. These data suggest that fish oil diet and ezetimibe in combination may be beneficial therapy for NAFLD by increasing hepatic Abcg5/g8 and decreasing lipogenic genes. SIGNIFICANCE STATEMENT: There is currently no single treatment for NAFLD. Thus, lifestyle modifications including dietary regulation and physical activity are also important options. In this study, ezetimibe, a cholesterol absorption inhibitor, was evaluated for the treatment of liver steatosis in rats fed on the different diets. We found that ezetimibe and fish oil in combination markedly improved fatty liver by increasing cholesterol efflux transporters. The combination therapy of fish oil agents and ezetimibe may be effective for NAFLD.
• Epidemiological and molecular characterization of invasive Streptococcus pneumoniae isolated following introduction of 7-valent conjugate vaccine in Kinki region, Japan, 2008-2013.

  Hirofumi Toda; Yuji Tanaka; Kaori Satoh; Masaru Komatsu; Yasunao Wada; Toru Tobe; Toshinori Kamisako

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 26 5 451 - 458 2020年05月 [査読有り]
   

  Streptococcus pneumoniae is one of the most common bacteria causing community-acquired pneumonia and meningitis. The use of 7-valent pneumococcal conjugate vaccine (PCV7) has reduced the incidence of pneumococcal disease while changing pneumococcal population through herd immunity and non-vaccine pneumococci replacement. This study investigated molecular epidemiologic characteristics of pneumococcal strains in the Kinki region of Japan from 2008 to 2013. A total of 159 invasive pneumococcal isolates were characterized by serotyping, antibiotic susceptibility testing, PCR analysis of penicillin-binding protein genes, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). In adult populations, pediatric PCV7 introduction decreased isolates expressing PCV7 serotypes via herd immunity and increased isolates expressing non-PCV7 serotypes. The rate of penicillin resistance and isolates with alterations in all three pbp genes was higher in PCV7 type isolates than in non-PCV7 type isolates. In MLST analysis, all of serotype 19F isolates were of the same sequence type, ST236, which is the antimicrobial-resistant clone Taiwan19F-14, and the majority of serotypes 23F and 19A isolates were of ST1437 and ST3111 respectively, which are the predominant clones of antimicrobial-resistant pneumococci in Japan. In PFGE profiles, serotype 6B-ST2224, serotype 19F-ST236, serotype 19A-ST3111, and serotype 23F-ST1437 formed six separate clusters composed of genetically identical strains, and genetically identical serotype 22F-ST433 formed two different clusters between the pre- and post-PCV7 period. The results of molecular analysis suggest the spread and persistence of these identical antimicrobial resistant clones in the Kinki region and genetic changes of epidemic clone serotype 22F-ST433 before and after pediatric PCV7 introduction.
• Laboratory surveillance of antimicrobial resistance and multidrug resistance among Streptococcus pneumoniae isolated in the Kinki region of Japan, 2001–2015

  Hirofumi Toda; Kaori Satoh; Masaru Komatsu; Saori Fukuda; Tatsuya Nakamura; Takumi Jikimoto; Hisaaki Nishio; Katsutoshi Yamasaki; Takuya Maede; Tamaki Orita; Noriyuki Sueyoshi; Machiko Kita; Masahiro Toyokawa; Isao Nishi; Masahiro Akagi; Takefumi Higuchi; Tomomi Kofuku; Isako Nakai; Tamotsu Ono; Koichi Shimakawa; Yoshie Hikita; Kunihiko Moro; Kaneyuki Kida; Masanobu Oohama; Yasunao Wada; Toru Tobe; Toshinori Kamisako; Yuji Tanaka

  Journal of Infection and Chemotherapy 24 3 171 - 176 2018年03月 [査読有り]
   

  The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced among children in Japan in 2010. There are no long-term multicenter surveillance studies of antimicrobial resistance in S. pneumoniae before and after the introduction of PCV7. Therefore, we examined chronological trends in antimicrobial resistance among 4534 strains of S. pneumoniae isolated from both children and adults in the Kinki region of Japan during 2001–2015. High-level penicillin and third-generation cephalosporin resistance in S. pneumoniae increased among both children and adults during the period before the introduction of PCV7 (2001–2010). Besides penicillin and cephalosporin, pneumococcal carbapenem and macrolide resistance increased among children. The rate of resistance to these antibiotics was higher among children than among adults. The introduction of PCV7 decreased the rate of non-susceptibility to β-lactam antibiotics and the rate of multidrug resistant S. pneumoniae among children, but not among adults.
• Gender-divergent expression of lipid and bile acid metabolism related genes in adult mice offspring of dams fed a high-fat diet.

  Yuji Tanaka; Takanori Ikeda; Shiori Masuda; Hiroshi Ogawa; Toshinori Kamisako

  J Biosci 43 2 329 - 337 2018年 [査読有り]
  
• 油脂源の違いが高フルクトース食摂取ラットの糖・脂質代謝に及ぼす影響

  柄本なつみ; 池田高紀; 梁川啓人; 田中裕滋; 上硲俊法; 小川博

  帝塚山学院大学人間科学部研究年報 19 134 - 152 帝塚山学院大学 2017年12月 

  高フルクトース食摂取ラットにおいて油脂源が大豆油の場合よりオリーブ油の場合の方が、血中トリグリセリド及び遊離脂肪酸濃度の上昇がもたらされ肝臓脂質が上昇することを報告した。
• 6-Methylsulfinylhexyl isothiocyanate prevents high-fat diet-induced fatty liver but fails to attenuate hepatic iron accumulation in mice

  Yuji Tanaka; Takanori Ikeda; Kazuo Yamamoto; Shiori Masuda; Hiroshi Ogawa; Toshinori Kamisako

  CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 43 11 1153 - 1156 2016年11月 [査読有り]
  
• Evaluation of menstrual cycle-related changes in 85 clinical laboratory analytes

  Shiori Masuda; Kiyoshi Ichihara; Hachiro Yamanishi; Yutaka Hirano; Yuji Tanaka; Toshinori Kamisako

  ANNALS OF CLINICAL BIOCHEMISTRY 53 3 365 - 376 2016年05月 [査読有り]
   

  Objective The menstrual cycle-related changes in clinical laboratory values were analysed by use of data obtained in the Asian multicentre study aimed at derivation of common reference intervals for 85 major clinical laboratory tests. Methods Among 1876 healthy female volunteers, 893 had regular menstruation. They were classified into five groups according to dates between sample collection and the start of the last menstrual cycle: early follicular phase (1-6 days), late follicular phase (7-12 days), ovulatory phase (13-16 days), early luteal phase (17-22 days), and late luteal phase (23-31 days). Multiple linear regression analysis was performed to evaluate the menstrual cycle-related changes in test results. The magnitude was expressed as a standard deviation ratio of between-phase standard deviation to between-individual standard deviation based on nested ANOVA. Results Aside from obvious changes for four sex hormones (oestradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone), we observed statistically significant menstrual cycle-related changes in the following tests (standard deviation ratio >0.15): Na, Cl, creatine kinase, C-reactive protein, serum amyloid A, carbohydrate antigen 125, and parathyroid hormone were higher during the early follicular phase, while insulin, total cholesterol, and white blood cell were higher during the luteal phase. Significant associations of those test items with the four sex hormones were revealed. Conclusions The menstrual cycle-related changes in laboratory test results were revealed in some commonly tested items other than sex hormones. The findings are of interest in understanding female physiology in relation to hormonal changes, but the magnitude of changes is rather small and not very relevant in interpreting test results.
• Geranium dielsianum extract powder (MISKAMISKA (TM)) improves the intestinal environment through alteration of microbiota and microbial metabolites in rats

  Takanori Ikeda; Yuji Tanaka; Kazuo Yamamoto; Hiroko Morii; Toshinori Kamisako; Hiroshi Ogawa

  JOURNAL OF FUNCTIONAL FOODS 11 12 - 19 2014年11月 [査読有り]
   

  Geranium dielsianum (GD) is a perennial plant found in the Andean highlands of Peru. Over the decades, the decoction of GD has been consumed as a tea protective against diabetes. Furthermore, GD has traditionally been used as an anti-diabetic, anti-inflammatory, and anti-diarrheal folk medicine. However, there is little scientific evidence elucidating its effects. This study aimed to test the effect of the GD extract on the intestinal environment. In male Sprague-Dawley rats, GD extract increased levels of Bifidobacteria and Lactobacilli and decreased levels of Clostridium leptum subgroup and Bacteroides group in the intestine. Furthermore, 3-hydroxyphenylacetic acid was present at high concentrations in the caecal content of GD extract intake group. Through the above changes in microbiota and microbial metabolites, faecal bulk and moisture increased and caecal pH and putrefactive products decreased. These results suggest that GD extract has a potent prebiotic effect. (C) 2014 The Authors. Published by Elsevier Ltd.
• Role of Nrf2 in the alteration of cholesterol and bile acid metabolism-related gene expression by dietary cholesterol in high fat-fed mice

  Toshinori Kamisako; Yuji Tanaka; Yoshizumi Kishino; Takanori Ikeda; Kazuo Yamamoto; Shiori Masuda; Hiroshi Ogawa

  JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION 54 2 90 - 94 2014年03月 [査読有り]
   

  Nuclear factor-E2-related factor 2 (Nrf2) is a regulator of lipid metabolism as well as various cytoprotective enzymes and may be involved in the pathogenesis of non-alcoholic fatty liver disease. Although, bile acids affect lipid metabolism, the role of Nrf2 in bile acid metabolism remains unclear. In this study, it was tested how Nrf2 modulates lipid and bile acid homeostasis in liver in response to changes of cholesterol absorption under high-fat diet using Nrf2-null mice. Eight-week-old male wild-type and Nrf2-null mice (n = 6/group) were divided into three groups fed the following diets: 1) control diet containing 4% soybean oil and 16% lard, 2) control diet plus ezetimibe, 3) control diet plus cholesterol. Blood and livers were removed after 4 weeks feeding. High cholesterol diet increased hepatic expression of liver X receptor a target genes related to fatty acid metabolism (FAS, ACC1, SREBP-1c, SCD-lc and CD36), cholesterol transport (Abcg5/abcg8) and bile acid synthesis (Cyp7a1) in wild type mice. However, these genes were not induced in Nrf2-null mice. These findings suggest that Nrf2 has a relation to liver X receptor a and controls the regulation of gene expressions related to lipid and bile acid metabolism.
• [Relationship between serum hCG and urinary hCG in cases of pregnancy, abortion, and hydatidiform mole].

  Kishino Y; Tanaka Y; Nakae K; Iwatani Y; Kamisako T

  Rinsho byori. The Japanese journal of clinical pathology 62 1 38 - 44 日本臨床検査医学会事務所 ; 1953- 2014年01月 [査読有り]
  
• Ezetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet

  Yoshizumi Kishino; Yuji Tanaka; Takanori Ikeda; Kazuo Yamamoto; Hiroshi Ogawa; Yoshinori Iwatani; Toshinori Kamisako

  JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 345 3 483 - 491 2013年06月 [査読有り]
   

  Accumulating evidence suggests that ezetimibe may be a promising agent for treatment of nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). Phlebotomy and dietary iron restriction reduce serum transaminase in NAFLD/NASH patients. Recent studies have shown that a mutual effect exists between lipid metabolism and iron metabolism. Accordingly, we examined the effect of ezetimibe on iron metabolism in mice fed a high-fat diet with or without iron. We fed C57BL/6 mice the following diets for 12 weeks. Experiment 1 comprised [1] a control diet (C), [2] C plus ezetimibe (0.3 mg/day; 4 weeks) (CE), [3] a high-fat diet (H), and [4] H plus ezetimibe (HE). Experiment 2 comprised [1] C containing carbonyl iron (average; 22.4 mg/day; 6 weeks) (CI), [2] CI plus ezetimibe (CIE), [3] H containing carbonyl iron (HI), and [4] HI plus ezetimibe (HIE). Blood, livers, and duodenum were removed after 12 weeks. In experiment 1, the hepatic iron levels were higher in HE than H, whereas there was no difference between C and CE. Hepatic mRNA expression of transferrin receptor 1 and 2, ferritins, and hepcidin were increased more in CE than C, and more in HE than H. In the duodenum, divalent metal transporter 1, ferritin H, and hephaestin mRNA levels were increased in CE compared with C. In experiment 2, hepatic iron concentrations were higher in HIE than HI. Hepatic mRNA expression of ferritin L and hepcidin were increased in HIE compared with HI. In duodenum, ferritin L mRNA was increased in HIE compared with CIE. Ezetimibe induced hepatic iron uptake transporter expression in mice fed a high-fat diet, causing increased hepatic iron concentrations.
• Relationship between Serum Bilirubin and Remnant Lipoprotein Cholesterol Level

  Toshinori Kamisako; Shiori Masuda; Yuji Tanaka

  CLINICAL LABORATORY 59 3-4 435 - 438 2013年 [査読有り]
   

  Background: Bilirubin has antioxidant properties and is known to have a role in the prevention of cardiovascular disease. Bilirubin is known to be negatively associated with serum parameters related to atherosclerosis. Triglyceriderich lipoprotein is known to play an important role in the progression of atherosclerosis. The aim of the present study was to elucidate the relationship between serum bilirubin and serum remnant lipoprotein cholesterol (RLP-c). Methods: We examined 270 Japanese males (mean age 64.8 years) without liver dysfunction and anemia from the Outpatient Clinic of Kinki University Hospital. Serum bilirubin, cholesterol, LDL cholesterol, HDL cholesterol, triglyceride and RLP-c levels were measured. Results: Serum RIP-c level was significantly lower in patients in the high bilirubin group than those in the low bilirubin group. Conclusions: The findings of this study show that serum bilirubin within physiological levels may affect the serum RLP-c and suggest bilirubin may have a role in preventing atherosclerosis.
• Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice

  Yuji Tanaka; Takanori Ikeda; Kazuo Yamamoto; Hiroshi Ogawa; Toshinori Kamisako

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 27 11 1711 - 1717 2012年11月 [査読有り]
   

  Background and Aim: Hepatic excessive iron may play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Nrf2 is a master regulator of antioxidative responses. However, the role of Nrf2 in lipid and iron homeostasis remains unclear. Accordingly, it was examined how Nrf2 regulates lipid-related and iron-regulatory genes after feeding a high-fat diet (HFD) with iron. Methods: Wild-type and Nrf2-null mice were fed the following diets: (i) control diet (4% soybean oil) for 12 weeks, (ii) control diet for 8 weeks followed by control diet containing 0.5% carbonyl iron for 4 weeks, (iii) HFD (4% soybean oil and 16% lard) for 12 weeks, (iv) HFD for 8 weeks followed by HFD containing 0.5% carbonyl iron for 4 weeks. Blood and livers were removed after 12 weeks. Results: Nrf2-null control mice exhibited a tendency towards higher hepatic triglycerides compared to wild-type control mice. Hepatic malondialdehyde was higher and hepatic iron levels tended to be higher in Nrf2-null mice than wild-type counterparts while on a HFD. The HFD with iron synergistically induced mRNA expression of Ppara targets, including Acox and Cpt1 in wild-type mice, yet the induction was diminished in Nrf2-null mice. Hepatic hepcidin and ferroportin 1 mRNA expression were increased in wild-type mice after feeding a HFD with iron, but were unchanged in any group of Nrf2-null mice. Conclusions: Nrf2 deletion dysregulates hepatic mRNA expression of beta-oxidation enzymes and iron-related genes, possibly causing a trend for increased hepatic triglyceride and iron concentrations. Nrf2 may have roles in the progression of NASH.
• Bile acids via FXR initiate the expression of major transporters involved in the enterohepatic circulation of bile acids in newborn mice

  Julia Yue Cui; Lauren M. Aleksunes; Yuji Tanaka; Zidong Donna Fu; Ying Guo; Grace Liejun Guo; Hong Lu; Xiao-bo Zhong; Curtis D. Klaassen

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 302 9 G979 - G996 2012年05月 [査読有り]
   

  Cui JY, Aleksunes LM, Tanaka Y, Fu ZD, Guo Y, Guo GL, Lu H, Zhong X, Klaassen CD. Bile acids via FXR initiate the expression of major transporters involved in the enterohepatic circulation of bile acids in newborn mice. Am J Physiol Gastrointest Liver Physiol 302: G979-G996, 2012. First published January 19, 2012; doi:10.1152/ajpgi.00370.2011.-The enterohepatic circulation (EHC) of bile acids (BAs) plays a pivotal role in facilitating lipid absorption. Therefore, initiation of the EHC in newborns is of crucial importance for lipid absorption from milk. The purpose of this study was to determine at what age BA transporters in liver are expressed, and the mechanism for their initiation. Serum and liver samples were collected from C57BL/6 mice at 2 days before birth and various postnatal ages. Messenger RNA assays revealed a dramatic increase at birth in the expression of the BA transporters (Ntcp, Bsep, Mrp4, Ost beta), as well as the phospholipid floppase Mdr2 in mouse liver, with the highest expression at 1 day of age. The mRNA expression of the ileal BA transporters (Ost alpha and Ost beta) also markedly increased at birth. Meanwhile, taurine-conjugated cholic acid markedly increased in both serum and liver of newborns, correlated with upregulation of the classic pathway of BA biosynthesis in newborn liver. The mRNA levels of the major BA sensors, FXR and PXR, were increased at 1 day of age, and their prototypical target genes were upregulated in liver. The mRNA expression of transporters involved in the EHC of BAs was similar in wild-type and PXR-null mice. In contrast, in FXR-null mice, the "day 1 surge" pattern of Ntcp, Bsep, Ost beta, and Mdr2 was blocked in newborn mouse liver, and the induction of Ost alpha and Ost beta was also abolished in ileums of FXR-null mice. In conclusion, at birth, BAs from the classic pathway of synthesis trigger the induction of transporters involved in EHC of BAs in mice, through activation of the nuclear receptor FXR.
• Dietary fish oil regulates gene expression of cholesterol and bile acid transporters in mice

  Toshinori Kamisako; Yuji Tanaka; Takanori Ikeda; Kazuo Yamamoto; Hiroshi Ogawa

  HEPATOLOGY RESEARCH 42 3 321 - 326 2012年03月 [査読有り]
   

  Aim: Fish oil rich in n-3 polyunsaturated fatty acids is known to affect hepatic lipid metabolism. Several studies have demonstrated that fish oil may affect the bile acid metabolism as well as lipid metabolism, whereas only scarce data are available. The aim of this study was to investigate the effect of fish oil on the gene expression of the transporters and enzymes related to bile acid as well as lipid metabolism in the liver and small intestine. Methods: Seven-week old male C57BL/6 mice were fed diets enriched in 10% soybean oil or 10% fish oil for 4 weeks. After 4 weeks, blood, liver and small intestine were obtained. Results: Hepatic mRNA expression of lipids (Abcg5/8, multidrug resistance gene product 2) and bile acids transporters (bile salt export pump, multidrug resistance associated protein 2 and 3, organic solute transporter a) was induced in fish oil-fed mice. Hepatic Cyp8b1, Cyp27a1 and bile acid CoA : amino acid N-acyltransferase were increased in fish oil-fed mice compared with soybean-oil fed mice. Besides, intestinal cholesterol (Abcg5/8) and bile acid transporters (multidrug resistance associated protein 2 and organic solute transporter a) were induced in fish oil-fed mice. Conclusion: Fish oil induced the expression of cholesterol and bile acid transporters not only in liver but in intestine. The upregulation of Abcg5/g8 by fish oil is caused by an increase in cellular 27-HOC through Cyp27a1 induction. The hepatic induction of bile acid synthesis through Cyp27a1 may upregulate expression of bile acid transporters in both organs.
• Danazol falsely increased values in estradiol immunoassays

  Yoshizumi Kishino; Yuji Tanaka; Shouchi Naitoh; Toshinori Kamisako

  CLINICA CHIMICA ACTA 411 17-18 1380 - 1381 2010年09月 [査読有り]
  
• Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

  Yu-Kun Jennifer Zhang; Ronnie L. Yeager; Yuji Tanaka; Curtis D. Klaassen

  TOXICOLOGY AND APPLIED PHARMACOLOGY 245 3 326 - 334 2010年06月 [査読有り]
   

  Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an-important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gst alpha 1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities. (C) 2010 Published by Elsevier Inc.
• Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

  Ivan L. Csanaky; Lauren M. Aleksunes; Yuji Tanaka; Curtis D. Klaassen

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 297 3 G419 - G433 2009年09月 [査読有り]
   

  Csanaky IL, Aleksunes LM, Tanaka Y, Klaassen CD. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol 297: G419-G433, 2009. First published June 4, 2009; doi: 10.1152/ajpgi.90728.2008.-The entero-hepatic recirculation of bile acids (BAs) is important in several physiological processes. Although there has been considerable research on liver regeneration after two-thirds partial hepatectomy (PHx), little is known about how the liver protects itself against BA toxicity during regeneration. In this study, various BAs in plasma and liver, the composition of micelle-forming bile constituents, as well as gene expression of the main hepatobiliary transporters were quantified in sham-operated and PHx mice 24 and 48 h after surgery. PHx did not influence the hepatic concentrations of taurine-conjugated BAs (T-BA) but increased the concentration of glycine-conjugated (G-BA) and unconjugated BAs. Total BA excretion (mu g . min(-1) . g liver wt(-1)) increased 2.4-fold and was accompanied by a 55% increase in bile flow after PHx. The plasma concentrations of T-BAs (402-fold), G-BAs (17-fold), and unconjugated BAs (500-fold) increased. The mRNA and protein levels of the BA uptake transporter Ntcp were unchanged after PHx, whereas the canalicular Bsep protein increased twofold at 48 h. The basolateral efflux transporter Mrp3 was induced at the mRNA (2.6-fold) and protein (3.1-fold) levels after PHx, which may contribute to elevated plasma BA and bilirubin levels. Biliary phospholipid excretion was nearly doubled in PHx mice, most likely owing to increased mRNA expression of the phospholipid transporter, Mdr2. In conclusion, the remnant liver after PHx excretes 2.5-fold more BAs and three times more phospholipids per gram liver than the sham-operated mouse liver. Upregulation of phospholipid transport may be important in protecting the biliary tract from BA toxicity during PHx.
• Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice

  Yue J. Cui; Lauren M. Aleksunes; Yuji Tanaka; Michael J. Goedken; Curtis D. Klaassen

  TOXICOLOGICAL SCIENCES 110 1 47 - 60 2009年07月 [査読有り]
   

  Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) are two major bile acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48 h later for hepatotoxicity and messenger RNA (mRNA) expression of basolateral uptake (sodium taurocholate-cotransporting polypeptide, organic anion transporting polypeptide [Oatp] 1a1, Oatp1a4, Oatp1b2) and efflux transporters (organic solute transporter [Ost] alpha, Ost beta, multidrug resistance-associated protein [Mrp] 3, Mrp4), as well as canalicular transporters (bile salt export pump [Bsep], Mrp2, multidrug resistance protein 2 [Mdr2], ATPase, class I, type 8B, member 1 [Atp8b1]). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48 h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice but failed to upregulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ost beta and Mrp3 mRNA in livers of wild-type and PXR-null mice but did not alter Ost beta mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.
• ANIT-Induced Intrahepatic Cholestasis Alters Hepatobiliary Transporter Expression via Nrf2-Dependent and Independent Signaling

  Yuji Tanaka; Lauren M. Aleksunes; Yue Julia Cui; Curtis D. Klaassen

  TOXICOLOGICAL SCIENCES 108 2 247 - 257 2009年04月 [査読有り]
   

  Alpha-naphthylisothiocyanate (ANIT) causes intrahepatic cholestasis by injuring biliary epithelial cells. Adaptive regulation of hepatobiliary transporter expression has been proposed to reduce liver injury during cholestasis. Recently, the oxidative stress transcription factor Nrf2 (nf-e2-related factor 2) was shown to regulate expression of hepatobiliary transporters. The purpose of this study was to determine whether ANIT-induced hepatotoxicity and regulation of hepatobiliary transporters are altered in the absence of Nrf2. For this purpose, wild-type and Nrf2-null mice were administered ANIT (75 mg/kg po). Surprisingly, ANIT-induced hepatotoxicity was similar in both genotypes at 48 h. Accumulation of bile acids in serum and liver was lower in Nrf2-null mice compared with wild-types treated with ANIT. Transporter mRNA profiles differed between wild-type and Nrf2-null mice after ANIT. Bsep (bile salt export pump), Mdr2 (multidrug resistance gene), and Mrp3 (multidrug resistance-associated protein) efflux transporters were increased by ANIT in wild-type, but not in Nrf2-null mice. In contrast, mRNA expression of two hepatic uptake transporters, Ntcp (sodium-taurocholate cotransporting polypeptide) and Oatp1b2 (organic anion transporting peptide), were decreased in both genotypes after ANIT, with larger declines in Nrf2-null mice. mRNA expression of the transcriptional repressor of Ntcp, small heterodimeric partner (SHP), was increased in Nrf2-null mice after ANIT. Furthermore, hepatocyte nuclear factor 1 alpha (HNF1 alpha), which regulates Oatp1b2, was downregulated in ANIT-treated Nrf2-null mice. Preferential upregulation of SHP and downregulation of HNF1 alpha and uptake transporters likely explains why Nrf2-null mice exhibited similar injury to wild-types after ANIT. A subsequent study revealed that treatment of mice with the Nrf2 activator oltipraz protects against ANIT-induced histological injury. Despite compensatory changes in Nrf2-null mice to limit ANIT toxicity, pharmacological activation of Nrf2 may represent a therapeutic option for intrahepatic cholestasis.
• CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes

  Scott A. Reisman; David B. Buckley; Yuji Tanaka; Curtis D. Klaassen

  TOXICOLOGY AND APPLIED PHARMACOLOGY 236 1 109 - 114 2009年04月 [査読有り]
   

  CDDO-Im is a synthetic triterpenoid recently shown to induce cytoprotective genes through the Nrf2-Keap1 pathway, an important mechanism for the induction of cytoprotective genes in response to oxidative stress. Upon oxidative or electrophilic insult, the transcription factor Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements (AREs) in the upstream promoter regions of various cytoprotective genes. To further elucidate the hepatoprotective effects of CDDO-Im, wild-type and Nrf2-null mice were pretreated with CDDO-Im (1 mg/kg, i.p.) or vehicle (DMSO), and then administered acetaminophen (500 mg/kg, i.p.). Pretreatment of wild-type mice with CDDO-Im reduced liver injury caused by acetaminophen. In contrast, hepatoprotection by CDDO-Im was not observed in Nrf2-null mice. CDDO-Im increased Nrf2 protein expression and Nrf2-ARE binding in wild-type, but not Nrf2-null mice. Furthermore, CDDO-Im increased the mRNA expression of the Nrf2 target genes NAD(P)H: quinone oxidoreductase-1 (Nqo1); glutamate-cysteine ligase, catalytic subunit (Gclc); and heme-oxygenase-1 (Ho-1), in both a dose- and time-dependent manner. Conversely, CDDO-Im did not induce Nqo1, Gclc, and Ho-1 mRNA expression in Nrf2-null mice. Collectively, the present study shows that CDDO-Im pretreatment induces Nrf2-dependent cytoprotective genes and protects the liver from acetaminophen-induced hepatic injury. (C) 2009 Elsevier Inc. All rights reserved.
• 第５４回日本臨床検査医学会近畿支部例会 シンポジウム 臨床検査からみた生活習慣病 司会のことば

  田中 裕滋; 森嶋 祥之; 上硲 俊法

  臨床病理 57 11 1064 - 1065 日本臨床検査医学会事務所 2009年
• Hepatic effects of a methionine-choline-deficient diet in hepatocyte RXR alpha-null mice

  Maxwell Afari Gyamfi; Yuji Tanaka; Lin He; Curtis D. Klaassen; Yu-Jui Yvonne Wan

  TOXICOLOGY AND APPLIED PHARMACOLOGY 234 2 166 - 178 2009年01月 [査読有り]
   

  Retinoid X receptor-alpha (RXR alpha) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXR alpha deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXR alpha-null (H-RXR alpha-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid beta-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXR alpha-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXR alpha-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXR alpha-null mice, the MCD diet only moderately decreased Oat1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXR alpha-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXR alpha-null mice. In conclusion, these data suggest a critical role for RXR alpha in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury. (C) 2008 Elsevier Inc. All rights reserved.
• Nrf2-and PPAR alpha-Mediated Regulation of Hepatic Mrp Transporters after Exposure to Perfluorooctanoic Acid and Perfluorodecanoic Acid

  Jonathan M. Maher; Lauren M. Aleksunes; Matthew Z. Dieter; Yuji Tanaka; Jeffrey M. Peters; Jose E. Manautou; Curtis D. Klaassen

  TOXICOLOGICAL SCIENCES 106 2 319 - 328 2008年12月 [査読有り]
   

  Perfluorooctanoic acid and perfluorodecanoic acid (PFDA) are commonly used as emulsifiers and surfactants in fluoropolymer manufacturing and are known peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists. PPAR alpha activation induces beta- and omega-oxidation enzymes such as Cyp4a14 and acyl-CoA oxidase, which are a likely cause of subsequent oxidative stress and peroxisome proliferation. Conversely, NF-E2-related factor-2 (Nrf2) is a transcription factor that protects against oxidative stress and inflammation by regulating several detoxification and xenobiotic transporter genes. Because PFDA markedly induces hepatic metabolism and oxidative stress, we hypothesized that PFDA exposure would increase expression of hepatic efflux multidrug resistance-associated protein (Mrp) transporters. A single PFDA dose (80 mg/kg) administered to mice increased hepatic Mrp3 (fourfold) and Mrp4 (31-fold) mRNA expression. Upregulation of Mrp3 and Mrp4 correlated with elevated serum-conjugated bilirubin and bile acids, respectively. To determine the mechanism of Mrp3 and Mrp4 induction, PFDA was administered to Nrf2-null mice, PPAR alpha-null mice, and mice pretreated with gadolinium chloride, a Kupffer cell-depleting chemical capable of inhibiting the inflammatory cytokine response. In both PPAR alpha- and Nrf2-null mice, maximal induction of Mrp3 and Mrp4 mRNA after PFDA administration was attenuated. Gadolinium chloride pretreatment reduced serum and hepatic tumor necrosis factor-alpha levels after PFDA treatment, as well as Mrp4 mRNA expression by 30%, suggesting that Kupffer cell-derived mediators may contribute to Mrp induction. Thus, after PFDA administration, the liver mounts a compensatory hepatoprotective response via PPAR alpha and Nrf2, markedly increasing Mrp3 and Mrp4 expression, with corresponding increases in serum of known Mrp3 and Mrp4 substrates.
• 血中および尿中に低分子IgMが出現した混合型クリオグロブリン血症の一例

  井本 真由美; 古垣内 美智子; 森嶋 祥之; 内藤 昭智; 上硲 俊法; 田中 裕滋; 豊増 麻美; 塩山 実章; 楠 進; 鮫島 謙一; 船内 正憲; 櫻林 郁之介

  臨床病理 56 補冊 149 - 149 (一社)日本臨床検査医学会 2008年10月
• Coordinated induction of Nrf2 target genes protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity

  Yuji Tanaka; Lauren M. Aleksunes; Michael J. Goedken; Chuan Chen; Scott A. Reisman; Jose E. Manautou; Curtis D. Klaassen

  TOXICOLOGY AND APPLIED PHARMACOLOGY 231 3 364 - 373 2008年09月 [査読有り]
   

  The iron chelate, ferric nitrilotriacetate (FeNTA), induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage. Chronic exposure of FeNTA leads to a high incidence of renal adenocarcinomas in rodents. NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles, and regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. To determine the roles of Nrf2 in regulating renal gene expression and protecting against oxidative stress-induced kidney damage, wild-type and Nrf2-null mice were administered FeNTA. Renal Nrf2 protein translocated to the nucleus at 6h after FeNTA treatment. FeNTA increased mRNA levels of Nrf2 target genes, including NQO1, GCLC, GSTpi 1/2, Mrp1, 2, and 4 in kidneys from wild-type mice, but not Nrf2-null m ice. Protein expression of NQO1, a prototypical Nrf2 target gene, was increased in wild-type in ice, with no change in Nrf2-null mice. FeNTA produced more nephrotoxicity in Nrf2-null mice than wild-type mice as indicated by higher serum Urea nitrogen and creatinine levels, as more urinary NAG, stronger 4-hydroxynonenal protein adduct staining, and more extensive proximal tubule damage. Furthermore, pretreatment with CDDO-lm, a potent small molecule Nrf2 activator, protected mice against FeNTA-induced renal toxicity. Collectively, these results suggest that activation of Nrf2 Protects mouse kidneys from FeNTA-induced oxidative stress damage by coordinately up-regulating the expression of cytoprotective genes. (C) 2008 Elsevier Inc. All rights reserved.
• NF-E2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet

  Yuji Tanaka; Lauren M. Aleksunes; Ronnie L. Yeager; Maxwell A. Gyamfi; Noriko Esterly; Grace L. Guo; Curtis D. Klaassen

  JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 325 2 655 - 664 2008年05月 [査読有り]
   

  NF-E2-related factor 2 (Nrf2) is a transcription factor that is activated by oxidative stress and electrophiles that regulates the expression of numerous detoxifying and antioxidant genes. Previous studies have shown that Nrf2 protects the liver from xenobiotic toxicity; however, whether Nrf2 plays a role in lipid homeostasis in liver is not known. Accordingly, wild-type and Nrf2-null mice were fed a high-fat diet (HFD) for up to 4 weeks. Hepatic gene expression and lipid profiles were analyzed for changes in fatty acid, triglyceride, and cholesterol status. It is interesting to note that HFD reduced the mRNA expression of Nrf2 and its target genes in wild-type mice. The mRNA expression of lipogenic and cholesterologenic transcriptional factors and their target genes, such as sterol regulatory element-binding proteins 1c and 2, fatty acid synthase, acetyl-CoA carboxylase 1, fatty acid elongase, 3-hydroxy-3-methyl-glutaryl coenzyme A synthase and reductase, and low-density lipoprotein receptor mRNA expression were higher in Nrf2-null mice compared with wild-type mice after feeding a HFD, suggesting that Nrf2 may suppress these pathways. Hepatic triglycerides and cholesterol levels were not different between genotypes, whereas concentrations of hepatic free fatty acid and malondialdehyde equivalents were higher in Nrf2-null mice compared with wild-type mice 4 weeks after HFD feeding. Overall, these results suggest that Nrf2 inhibits lipid accumulation and oxidative stress in mouse liver after feeding a HFD, probably by interfering with lipogenic and cholesterologenic pathways.
• Ischemia-reperfusion of rat livers decreases liver and increases kidney multidrug resistance-associated protein 2 (Mrp2)

  Yuji Tanaka; Chuan Chen; Jonathan M. Maher; Curtis D. Klaassen

  TOXICOLOGICAL SCIENCES 101 1 171 - 178 2008年01月 [査読有り]
   

  Hepatic ischemia-reperfusion (IR) injury during liver transplantation can lead to cholestasis and remote organ dysfunction. Multidrug resistance-associated proteins (Mrps) are efflux transporters known to transport a diverse set of substrates, such as amphipathic chemicals, organic anions, and endogenous molecules. The purpose of this study was to determine the effect of hepatic IR injury on the expression of Mrps in rat liver and kidney. Male Sprague-Dawley rats were subjected to 60 min of partial hepatic ischemia. At various times after reperfusion (0, 3, 6, 24, and 48 h), the ischemic lobes were harvested as well as kidneys. RNA and protein expression of Mrps in livers and kidneys were determined by the branched DNA method, Western blot analysis, and tissue immunofluorescence. Mrp2 mRNA and protein expression in livers decreased after IR. Conversely, Mrp2 mRNA and protein expression in kidneys increased after IR. Mrp3 mRNA expression, and Mrp4 mRNA and protein expression in kidneys transiently increased after IR. The intensity of immunofluorescent staining of Mrp2 corresponded to changes in Mrp2 expression in livers and kidneys after IR as detected by Western blot analysis and was localized to the apical membrane domain in both tissues. These results demonstrate that after hepatic IR, downregulation of hepatic Mrp2 and upregulation of renal Mrp2 occur. These decreases in hepatic Mrp2 may contribute to cholestasis, yet increases in kidney may protect from oxidative stress and/or inflammation after hepatic IR.
• Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway

  Jonathan M. Maher; Matthew Z. Dieter; Lauren M. Aleksunes; Angela L. Slitt; Grace Guo; Yuji Tanaka; George L. Scheffer; Jefferson Y. Chan; Jose E. Manautou; Ying Chen; Timothy P. Dalton; Masayuki Yamamoto; Curtis D. Klaassen

  HEPATOLOGY 46 5 1597 - 1610 2007年11月 [査読有り]
   

  Multidrug resistance-associated proteins (Mrps) are adenosine triphosphate- dependent transporters that efflux chemicals out of cells. In the liver, Mrp2 transports bilirubin-glucuronide, glutathione (GSH), and drug conjugates into bile, whereas Mrp3 and Mrp4 efflux these entities into blood. The purpose of this study was to determine whether oxidative conditions (that is, the disruption of hepatic GSH synthesis) or the administration of nuclear factor-E2-related factor-2 (Nrf2) activators (oltipraz and butylated hydroxyanisole) can induce hepatic Mrp, transporters and whether that induction is through the Nrf2 transcriptional pathway. Livers from hepatocyte-specific glutamate-cysteine ligase catalytic subunit-null mice had increased nuclear Nrf2 levels, marked gene and protein induction of the Nrf2 target gene NAD(P)H:quinone oxidoreductase 1, as well as Mrp2, Mrp3, and Mrp4 expression. The treatment of wild-type and Nrf2-null mice with oltipraz and butylated hydroxyanisole demonstrated that the induction of Mrp,2, Mrp3, and Mrp4 is Nrf2-dependent. In Hepa1c1c7 cells treated with the Nrf2 activator tert-butyl hydroquinone, chromatin immunoprecipitation with Nrf2 antibodies revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of mouse Mrp2 [-185 base pairs (bp)], Mrp3 (-9919 bp), and Mrp4 (-3767 bp). Conclusion: The activation of the Nrf2 regulatory pathway stimulates the coordinated induction of hepatic Mrps.
• Activation of cAMP-dependent signaling pathway induces mouse organic anion transporting polypeptide 2 expression

  Chuan Chen; Xingguo Cheng; Matthew Z. Dieter; Yuji Tanaka; Curtis D. Klaassen

  MOLECULAR PHARMACOLOGY 71 4 1159 - 1164 2007年04月 [査読有り]
   

  Rodent Oatp2 is a hepatic uptake transporter for such compounds as cardiac glycosides. In the present study, we found that fasting resulted in a 2-fold induction of Oatp2 expression in liver of mice. Because the cAMP-protein kinase A (PKA) signaling pathway is activated during fasting, the role of this pathway in Oatp2 induction during fasting was examined. In Hepa-1c1c7 cells, adenylyl cyclase activator forskolin as well as two cellular membrane-permeable cAMP analogs, dibutyryl cAMP and 8-bromo-cAMP, induced Oatp2 mRNA expression in a time- and dose-dependent manner. These three chemicals induced reporter gene activity in cells transfected with a luciferase reporter gene construct containing a 7.6-kilobase (kb) 5'-flanking region of mouse Oatp2. Transient transfection of cells with 5'-deletion constructs derived from the 7.6-kb Oatp2 promoter reporter gene construct, as well as 7.6-kb constructs in which a consensus cAMP response element (CRE) half-site CGTCA (-1808/-1804 bp) was mutated or deleted, confirms that this CRE site was required for the induction of luciferase activity by forskolin. Luciferase activity driven by the Oatp2 promoter containing this CRE site was induced in cells cotransfected with a plasmid encoding the protein kinase A catalytic subunit. Cotransfection of cells with a plasmid encoding the dominant-negative CRE binding protein (CREB) completely abolished the inducibility of the reporter gene activity by forskolin. In conclusion, induction of Oatp2 expression in liver of fasted mice may be caused by activation of the cAMP-dependent signaling pathway, with the CRE site (-1808/-1804) and CREB being the cis- and trans-acting factors mediating the induction, respectively.
• Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice

  Yuji Tanaka; Jonathan M. Maher; Chuan Chen; Curtis D. Klaassen

  MOLECULAR PHARMACOLOGY 71 3 817 - 825 2007年03月 [査読有り]
   

  Hepatic ischemia-reperfusion (IR) results in Kupffer cell activation and subsequent tumor necrosis factor (TNF) alpha release, leading to localized hepatic injury and remote organ dysfunction. Heme oxygenase (HO)-1 is an enzyme that is induced by various stimuli, including proinflammatory cytokines, and exerts antioxidative and anti-inflammatory functions. Up-regulation of HO-1 is known to protect against hepatic IR injury, but the effects of hepatic IR on the kidney are poorly understood. Thus, the purpose of this study was to determine whether hepatic IR and resultant Kupffer cell activation alters renal HO-1 expression. Male Sprague-Dawley rats and wild-type and NF-E2-related factor 2 (Nrf2)-null mice were subjected to 60 min of partial hepatic ischemia, and at various times thereafter, blood, liver, and kidneys were collected. After reperfusion, 1) creatinine clearance decreased; 2) HO-1 mRNA and protein expression in liver and kidney markedly increased; 3) renal NAD( P) H: quinone oxidoreductase 1 mRNA expression was induced; 4) serum TNF alpha levels increased; 5) Nrf2 translocation into the nucleus of renal tissue increased; and 6) renal and urinary 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)) levels increased. Kupffer cell depletion by pretreating with gadolinium chloride 1) attenuated increased mRNA expression of HO-1 in kidney; 2) attenuated the increase in TNF alpha; 3) inhibited the increase in Nrf2 nuclear translocation; and 4) tended to attenuate renal 15-d-PGJ(2) levels. Whereas renal HO-1 mRNA expression increased in wild-type mice, it was attenuated in Nrf2-null mice. These results suggest that renal HO-1 is induced via Nrf2 to protect the kidney from remote organ injury after hepatic IR.
• Kupffer cell-mediated downregulation of hepatic transporter expression in rat hepatic ischemia-reperfusion

  Yuji Tanaka; Chuan Chen; Jonathan M. Maher; Curtis D. Klaassen

  TRANSPLANTATION 82 2 258 - 266 2006年07月 [査読有り]
   

  Background. Hepatic ischemia-reperfusion (IR) injury is frequently followed by cholestatic liver disease. Cytokines released by Kupffer cells following hepatic IR injury may subsequently regulate hepatic transporter expression. The purpose of this study was to determine whether hepatic IR injury and the resultant Kupffer cell activation alters hepatic transporter expression. Methods. Rats were subjected to 60 minutes of partial hepatic ischemia followed by 0, 3, 6, 24, or 48 hours of reperfusion. After IR surgery, the following were determined: 1) serum bilirubin and bile acid levels; 2) serum levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL6; 3) expression of several hepatic transporters; and 4) nuclear protein levels of hepatocyte nuclear factor (HNF)-1 alpha and retinoid X receptor (RXR)-alpha to investigate whether altered expression of hepatic transporters following IR is associated with decreases in these transcription factors. Results. After reperfusion: 1) serum bilirubin and bile acids increased; 2) levels of all three cytokines increased; 3) mRNA expression of hepatic transporters organic anion transporting polypeptide (Oatp) 1a1, Oatp1a4, Oatp1b2, sodium taurocholate cotransporting polypeptide, multidrug resistance-associated protein (Mdr) 2, and bile salt export pump decreased, whereas Mdr1b expression increased; and 4) nuclear protein levels of HNF1 alpha decreased, whereas RXR alpha was not altered. Pretreatment with gadolinium chloride to deplete Kupffer cells before IR: 1) blocked the increase in serum bile acids, 2) attenuated TNF alpha but not IL1 beta/IL6 levels, 3) inhibited the altered hepatic transporter expression, and 4) blocked the decrease in HNF1 alpha nuclear protein levels. Conclusions. These results suggest that alterations in hepatic transporter expression during IR occur through Kupffer cell-mediated events, possibly involving a decrease in nuclear HNF1 alpha.
• Hormonal regulation of renal multlidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) in mice

  JM Maher; Cheng, X; Y Tanaka; GL Scheffer; CD Klaassen

  BIOCHEMICAL PHARMACOLOGY 71 10 1470 - 1478 2006年05月 [査読有り]
   

  Multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) are expressed at much higher levels in female than male kidney. Sex steroids and sex-specific growth hormone (GH) secretion patterns often mediate gender-predominant gene expression. Thus, three models were used to investigate potential endocrine regulation of Mrp3 and Mrp4: (1) gonadectomized (GNX) mice with 17 beta-estradiol (E2) or 5 alpha-dihydroxytestosterone (DHT) replacement; (2) hypophysectomized (HPX) mice receiving E2, DHT, or simulated male-pattern (MP) or female-pattern (FP) GH secretion; (3) lit/lit mice, which have a spontaneous mutation in the growth-hormone releasing-hormone (GHRH) receptor, with simulated MP-or FP-GH secretion. GNX and HPX decreased Mrp3 mRNA levels compared with intact females. In both respective models E2 administration increased Mrp3 expression in GNX and HPX mice. DHT markedly repressed Mrp3 from GNX + placebo levels, however, this was not observed in the HPX model. In lit/lit mice, Mrp3 expression was lower than in wild-type controls, and MP-GH and FP-GH simulation slightly increased Mrp3 expression. Whereas GNX increased Mrp4 in males to female levels, HPX actually increased Mrp4 expression in both genders +375% and +66%, respectively. in both models DHT markedly repressed MrP4. Furthermore, Mrp4 was higher in lit/lit than wild-type male mice, and simulation of MP-GH secretion suppressed female-predominant Mrp4 expression. In conclusion, these data indicate that E2 contributes to higher Mrp3 mRNA expression in females, yet a role for androgens in Mrp3 repression cannot be discounted. In contrast, Mrp4 mRNA is higher in females due to repression by both DHT and MP-GH secretion in males. (c) 2006 Elsevier Inc. All rights reserved.
• Transfecting the multidrug resistance protein 2 gene improves transcellular organic anion transport

  T Itani; Y Kobayashi; M Kuroda; N Ma; R Mifuji; N Urawa; Y Tanaka; M Kaito; Y Adachi

  INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 16 5 821 - 825 2005年11月 [査読有り]
   

  Eisai hyperbilirubinuria rats (EHBRs) lack functionally active multidrug resistance protein 2 (Mrp2), which causes impaired biliary excretion of numerous organic anions. We previously reported that Mrp3 expression is enhanced while organic anion transporting polypeptide I (Oatp1) or Oatp2 expression is reduced in the liver of EHBRs. Mrp3 mediates basolateral efflux of organic anions but not canalicular export. In this study, we transfected the human MRP2 gene into the liver of EHBRs and evaluated whether its transfection improves transcellular transport of organic anions in hepatocytes of EHBRs. The protein expression vector (pDEST(26)) including the full-length human MRP2 cDNA was developed. This vector was mixed with the hemagglutinating virus of Japan (HJV) envelope protein and transfected into the liver of EHBRs via the portal vein. Expression of Mrp3, Oatpl and Oatp2 was evaluated by reverse transcription-polymerase chain reaction and Western blot analysis. mRNA and protein expression of MRP2 were detected in hepatocytes from transfected EHBRs. The serumconjugated bilirubin level in EHBRs decreased to a normal level (35.7 to 6.4 mu mol/l) with the expression of human MRP2. The change in expression of Mrp3, Oatpl and Oatp2 in the liver of EHBRs was normalized by transfecting MRP2. Transfection of human MRP2 was performed using the HJV envelope protein. Transfection of MRP2 is useful for improving the transcellular transport of organic anions in the livers of EHBRs.
• Up-regulation of Mrp4 expression in kidney of Mrp2-deficient TR- rats

  CA Chen; AL Slitt; MZ Dieter; Y Tanaka; GL Scheffer; CD Klaassen

  BIOCHEMICAL PHARMACOLOGY 70 7 1088 - 1095 2005年10月 [査読有り]
   

  Multidrug resistance-associated proteins (Mrps) are a group of ATP-dependent efflux transporters for organic anions. Mrp2 and Mrp4 are co-localized to the apical (brush-border) membrane domain of renal proximal tubules, where they may function together in the urinary excretion of organic. anions. Previous reports showed that urinary excretion of some organic anions is not impaired in transport-deficient TR- rats, which lack Mrp2, suggesting that up-regulation of other transporter(s) may compensate for the loss of Mrp2 function. The purpose of this study was to determine whether Mrp4 expression in kidney is altered in TR- rats. Mrp4 mRNA expression was quantified using the high-throughput branched DNA signal amplification assay. Mrp4 protein expression was determined by Western blot and imunohistochemical analysis. Mrp4 mRNA in kidney of TR- rats was 100% higher than normal Wistar rats. Western blot analysis showed a 200% increase in Mrp4 protein expression in kidney of the mutant rats compared to normal rats. Immunohistochemical analysis of Mrp4 protein demonstrated apical localization of Mrp4 on renal proximal tubules, and that the immunoreactivity was more intense in kidney sections from TR- rats than those from normal rats. In summary, the results of the present study demonstrate that renal Mrp4 expression is up-regulated in TR_- rats, which may explain why urinary excretion of some organic anions remains normal in the mutant rats. (c) 2005 Elsevier Inc. All rights reserved.
• Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice

  Y Tanaka; AL Slitt; TM Leazer; JM Maher; CD Klaassen

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 326 1 181 - 187 2005年01月 [査読有り]
   

  Breast cancer resistance protein (Bcrp/Abcg2) is a member of the ABC transporter family. The purpose of this study was to quantify Bcrp mRNA in rat and mouse tissues, and to determine whether there are gender differences in Bcrp mRNA expression. Rat Bcrp mRNA levels were high in intestine and male kidney, and intermediate in testes. Mouse Bcrp expression was highest in kidney, followed by liver, ileum, and testes. Male-predominant expression of Bcrp was observed in rat kidney and mouse liver. Furthermore, gonadectomy and hypophysectomy experiments were conducted to determine whether sex steroids and/or growth hormone are responsible for Bcrp gender-divergent expression patterns. Male-predominant expression of Bcrp in rat kidney appears to be due to the suppressive effect of estradiol, and male-predominant expression of Bcrp in mouse liver appears to be due to the inductive effect of testosterone. (C) 2004 Elsevier Inc. All rights reserved.
• Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats

  K Higuchi; Y Kobayashi; M Kuroda; Y Tanaka; T Itani; J Araki; R Mifuji; M Kaito; Y Adachi

  HEPATOLOGY RESEARCH 29 1 60 - 66 2004年05月 [査読有り]
   

  Background: Gunn rat is an animal model of Crigler-Najjar syndrome (CNS) type I that develops jaundice due to defect of bilirubin conjugation. Bilirubin UDP-glucuronosyltransferase (UGT1A1), which plays a critical role in bilirubin glucuronidation, has been reported to be deficient in CNS type 1. On the other hand, little is known about the expression of organic anion transporters in Gunn rats. In the present study, we evaluated expressions of organic anion transporting polypeptide (oatp) I and 2, multidrug resistance-associated protein (mrp) 2 and mrp3 in the liver and kidney of Gunn rats. Methods: Serum samples, liver and kidney tissues were obtained from Gunn rats and normal SD rats (n = 6, in each group). Semi-quantitative mRNA expression of oatp1, oatp2, mrp2, and mrp3 mRNA was evaluated by constructed reverse transcription-polymerase chain reaction (RT-PCR). Protein expressions were determined by Western blotting and by immunohistochemistry. Results: Marked elevation of serum unconjugated bilirubin concentration (129.4 +/- 34.8 mumol/l) was observed in Gunn rats. Hepatic expression of oatp1 and oatp2 mRNA was 44% (P < 0.01) and 35% (P < 0.01) lower in Gunn rats than in SD rats, respectively. Hepatic oatp1 protein expression was 37% (P < 0.05) lower in Gunn rats than in SD rats. In contrast to oatp I, hepatic expression of mrp3 mRNA and protein was 76% (P < 0.01) and 557% (P < 0.01) higher in Gunn rats than in SD rats, respectively. Hepatic expression of oatp2 and mrp2 protein was not significantly different between Gunn rats and SD rats. Like the Western blot analysis, immunohistochemical staining disclosed decrease of oatp I and increase of mrp3 protein expressions in the liver of Gunn rats. Decrease of oatp I and increase of mrp3 expressions were also observed in the kidney of Gunn rats. Conclusion: Decreased expression of oatp1 and increased expression of mrp3 were observed in the liver and kidney of Gunn rats. Deficient UGT1A1 activity-associated retention of unconjugated bilirubin in the hepatocytes may modulate the expressions of these transporters in Gunn rats. (C) 2004 Elsevier B.V. All rights reserved.
• Increased hepatic and renal expressions of multidrug resistance-associated protein 3 in Eisai hyperbilirubinuria rats

  M Kuroda; Y Kobayashi; Y Tanaka; T Itani; R Mifuji; J Araki; M Kaito; Y Adachi

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 19 2 146 - 153 2004年02月 [査読有り]
   

  Background and Aim: Eisai hyperbilirubinuria rats (EHBR) are animal models of Dubin-Johnson syndrome, which suffer from jaundice due to impaired biliary excretion of bilirubin glucuronides. In EHBR, deficiency of multidrug resistance-associated protein 2 (mrp2) causes defective biliary excretion of numerous organic anions. However, little is known about the expression of other organic anion transporters in this mrp2-deficient model. The aim of the present study was to investigate adaptive expressions of mrp1, mrp3, mrp6, organic anion transporting polypeptide 1 (oatp1) and oatp2 in liver and kidney of EHBR. Methods: For the present study, EHBR (n = 5) were used. Hepatic and renal mRNA expression of the aforementioned transporters was determined by constructed semiquantitative reverse transcription polymerase chain reaction assay. Their protein expression was determined by western blotting. Localization of hepatic and renal mrp3 was confirmed by immunohistochemistry. Sprague-Dawley (SD) rats (n = 5) were used as normal controls. Results: Deficiency of mrp2 protein was confirmed in EHBR. Hepatic and renal expression of mrp3 mRNA was 53.6% (P < 0.001) and 82.9% (P < 0.001), and its protein expression was 298.9% (P < 0.001) and 245.0% (P = 0.001) higher in EHBR than in SD rats, respectively. Hepatic and renal expression of mrp1 and mrp6 mRNA was not significantly different between EHBR and SD rats. The mrp1 and mrp6 proteins were expressed in very low amounts in the liver and kidney of both EHBR and SD rats. In contrast to mrp3, hepatic expression of oatp1 and oatp2 mRNA was 33.9% (P = 0.001) and 38.6% (P < 0.00 1), and their protein expression was 57.4% (P < 0.05) and 51.0% (P < 0.01) lower in EHBR than in SD rats, respectively. Hepatic and renal mrp3 protein was localized at the basolateral membrane. Conclusions: Mrp3 plays an important role in the compensation of mrp2 deficiency in liver and kidney of EHBR. Hepatic expressions of mrp3, oatp1 and oatp2 changed adaptively in this animal model. This is a compensatory mechanism for reducing injury to hepatocytes from cytotoxic materials that increase in mrp2 deficiency. (C) 2004 Blackwell Publishing Asia Pty Ltd.
• "Green juice" - Associated granulomatous hepatitis

  R Mifuji; M Iwasa; Y Tanaka; Y Hori; J Araki; M Kaito; Y Adachi

  AMERICAN JOURNAL OF GASTROENTEROLOGY 98 10 2334 - 2335 2003年10月 [査読有り]
  
• Expression of hepatobiliary organic anion transporters and bilirubin-conjugating enzyme in differentiating mouse embryonic stem cells.

  Y Kobayashi; Y Tanaka; M Yoshikawa; M Kuroda; T Itani; M Kaito; Ishizaka, I; Y Adachi

  HEPATOLOGY 38 4 286A - 286A 2003年10月 [査読有り]
  
• 分化誘導したHNF-3beta導入マウス胚性幹細胞における有機アニオントランスポーター及びbilirubin UDP-glucronosyltransferase発現の検討

  黒田 誠; 小林 由直; 田中 裕滋; 井谷 俊夫; 垣内 雅彦; 吉川 正英; 石坂 重昭; 足立 幸彦

  肝臓 44 Suppl.2 A466 - A466 (一社)日本肝臓学会 2003年09月
• Spirulina-associated hepatotoxicity

  M Iwasa; M Yamamoto; Y Tanaka; M Kaito; Y Adachi

  AMERICAN JOURNAL OF GASTROENTEROLOGY 97 12 3212 - 3213 2002年12月 [査読有り]
  
• Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice

  Y Tanaka; Y Kobayashi; EC Gabazza; K Higuchi; T Kamisako; M Kuroda; K Takeuchi; M Iwasa; M Kaito; Y Adachi

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 282 4 G656 - G662 2002年04月 [査読有り]
   

  Regulation of bilirubin glucuronide transporters during hyperbilirubinemia in hepatic and extrahepatic tissues is not completely clear. In the present study, we evaluated the regulation of the bilirubin glucuronide transporters, multidrug resistance-associated proteins (MRP)2 and 3, in rats with obstructive jaundice. Bile duct ligation (BDL) or sham operation was performed in Wistar rats. Liver and kidneys were removed 1, 3, and 5 days after BDL (n = 4, in each group). Serum and urine were collected to measure bilirubin levels just before animal killing. MRP2 And MRP3 mRNA expressions were determined by real-time RT-PCR. Protein expression of MRP2 and MRP3 was determined by Western blotting. Renal MRP2 function was evaluated by para-aminohippurate (PAH) clearance. The effect of conjugated bilirubin, unconjugated bilirubin, human bile, and sulfate-conjugated bile acid on MRP2 gene expression was also evaluated in renal and hepatocyte cell lines. Serum bilirubin and urinary bilirubin excretion increased significantly after BDL. In the liver, the mRNA expression of MRP2 decreased 59, 86, and 82%, and its protein expression decreased 25, 74, and 93% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. In contrast, the liver expression of MRP3 mRNA increased 138, 2,137, and 3,295%, and its protein expression increased 560, 634, and 612% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. On the other hand, in the kidneys, the mRNA expression of MRP2 increased 162, 73, and 21%, and its protein expression increased 387, 558, and 472% compared with sham-operated animals after 24, 72, and 120 h of BDL, respectively. PAH clearance was significantly increased after BDL. The mRNA expression of MRP2 increased in renal proximal tubular epithelial cells after treatment with conjugated bilirubin, sulfate-conjugated bile acid or human bile. Upregulation of MRP2 in the kidneys and MRP3 in the liver may be a compensatory mechanism to improve bilirubin clearance during obstructive jaundice.
• Dietary iron restriction improves aminotransferase levels in chronic hepatitis C patients

  M Iwasa; M Kaito; J Ikoma; Y Kobayashi; Y Tanaka; K Higuchi; K Takeuchi; K Iwata; S Watanabe; Y Adachi

  HEPATO-GASTROENTEROLOGY 49 44 529 - 531 2002年03月 [査読有り]
   

  Background/Aims: It is generally accepted that iron overload plays an important role in the pathogenesis of liver cell injury in chronic hepatitis C. The present study was undertaken to evaluate whether low-iron diet improves liver function tests in patients with chronic hepatitis C. Methodology: Seventeen patients with chronic hepatitis C (13 men and 4 women, 54 14 years old) that did not respond to, or were unsuitable for interferon therapy, were enrolled in this study. All patients had been pretreated with ursodeoxycholic acid for more than 12 months before the beginning of the study. Dietary iron intake was restricted to less than 7mg/day, and the patients were followed up for 18 months. Results: Mean daily iron intakes, calculated from food records, were 5.9 and 6.4mg after 6 and 12 months, respectively. The mean serum ferritin decreased significantly from 362ng/mL at entry to 179ng/mL after 18 months. The serum unsaturated iron binding capacity level increased significantly from 163mug/dL at entry to 203mug/dL after 18 months. The serum aspartate aminotransferase decreased significantly from 62 IU/L at entry to 47 IU/L after 18 months, and serum alanine aminotransferase from 68 IU/L at entry to 53 IU/L after 18 months. Serum iron, hepatitis C virus-RNA titer and platelet count remained unchanged throughout the study. Conclusions: These results suggest that iron-restricted diet may be an important therapeutic modality for improving liver injury in patients with chronic hepatitis C.
• Increased expression of multidrug resistance-associated protein I (mrp1) in hepatocyte basolateral membrane and renal tubular epithelia after bile duct ligation in rats

  QL Pei; Y Kobayashi; Y Tanaka; Y Taguchi; K Higuchi; M Kaito; N Ma; R Semba; T Kamisako; Y Adachi

  HEPATOLOGY RESEARCH 22 1 58 - 64 2002年01月 [査読有り]
   

  Components of the multidrug resistance-associated protein (mrp) family mediate the adenosine triphosphate (ATP)-dependent transport of conjugated organic anions in the liver. Of these, mrp1 and mrp2 hake been shown to have similar substrate specificity and nucleotide sequence, The intracellular localization and distribution of mrp1 under normal condition and cholestasis have not been as yet completely elucidated, To clarify this point, in the present study we evaluated the intracellular localization of mrp1 in rat liver and kidney after bile duct ligation (BDL). Bile duct was ligated in Wistar rats. Sequential staining of mrp1 by immunofluorescence was carried out in rat liver and kidneys 1, 3, and 5 days after bile duct ligation using confocal laser scanning microscopy. Weak granular staining of mrp1 was observed in cytoplasm of control rat hepatocytes. In addition to increased cytoplasm staining of mrp1, belt-and granule-like staining of mrp1 in basolateral membrane of hepatocytes was also shown after BDL. Furthermore, mrp1 immunofluorescence increased over time after BDL. No specific immunoflurescence of mrp1 was detected in control rat kidney. However. mrp1-positive staining was observed in epithelia of some renal tubules after BDL. This study showed that mrp1 immunofluorescence increased in hepatocyte basolateral membrane and cytoplasm and epithelia of some renal tubules after BDL. This increased mrp1 expression may be an adaptive response to impairment of hepato-biliary organic anion transport during obstructive cholestasis. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
• Rapid progress of acute suppurative cholangitis to secondary sclerosing cholangitis sequentially followed-up by endoscopic retrograde cholangiography

  Y Tanaka; H Koshiyama; K Nakao; Y Makita; Y Kobayashi; Y Yoshida; M Kimura; Y Adachi

  ENDOSCOPY 33 7 633 - 635 2001年07月 [査読有り]
   

  A 66-year-old man was admitted to our hospital because of right hypochondralgia and fever after colonic polypectomy. Endoscopic examination revealed purulent bile excretion from the duodenal papilla orifice; based on this finding, acute suppurative cholangitis was diagnosed. An endoscopic retrograde cholangiography revealed no abnormality in the biliary tree. However, chronic cholestasis persisted, and endoscopic cholangiography performed 4 months later disclosed a beaded appearance of the intrahepatic bile ducts; this sign is a characteristic finding of sclerosing cholangitis. This is the first report of rapid progression of acute suppurative cholangitis to secondary sclerosing cholangitis sequentially followed-up by endoscopic retrograde cholangiography.
• Role of UGT1A1 mutation in fasting hyperbilirubinemia

  T Ishihara; M Kaito; K Takeuchi; EC Gabazza; Y Tanaka; K Higuchi; J Ikoma; S Watanabe; H Sato; Y Adachi

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 16 6 678 - 682 2001年06月 [査読有り]
   

  Background and Aim: Low-grade fasting hyperbilirubinemia is a common observation in healthy subjects (HS), whereas high-grade fasting hyperbilirubinemia is believed to be a characteristic finding of Gilbert's syndrome. This study was undertaken to assess the role of mutation in bilirubin UDP-glycosyltransferase gene (UGT1A1) on fasting hyperbilirubinemia. Methods: Analysis of UGT1A1 and a caloric restriction test (400 kcal for 24 h) were performed in 56 healthy subjects (25 males, 31 females), and 28 patients with Gilbert's syndrome (18 males, 10 females). There were 29 healthy subjects with no mutation in UGT1A1, and 27 healthy subjects and 26 Gilbert's syndrome patients with mutations in the coding and/or promoter (TATA box) regions of UGT1A1. Results: The mean increment of serum bilirubin (DeltaSB) was 9.6 mumol/L (males) and 4.1 mumol/L (females) in subjects with no UGT1A1 mutation. Subjects with mutation in UGT1A1 showed higher levels of DeltaSB than individuals without mutation. Among healthy subjects, gender difference in DeltaSB values was observed only in individuals with the wild type of UGT1A1, but not in those with mutations in this gene. Conclusion: The results of the present study suggest that UGT1A1 mutation has a role in the development of high-grade fasting hyperbilirubinemia after caloric restriction. (C) 2001 Blackwell Science Asia Pty Ltd.
• 【肝病態生理研究のあゆみ】総胆管結紮ラットの肝及び腎におけるMultidrug Resistance-associated Protein 1(Mrp1)及びMrp2の組織内分布と細胞内局在に関する検討

  裴 秋玲; 小林 由直; 田中 裕滋; 田口 由紀子; 樋口 国博; 垣内 雅彦; 足立 幸彦; 馬 寧; 仙波 礼治; 上硲 俊法

  薬理と治療 29 Suppl.1 S115 - S118 ライフサイエンス出版(株) 2001年04月 

  雄性SDラットに総胆管結紮(BDL)を施行し胆汁うっ滞モデルを作製し,肝及び腎におけるmrp1及びmrp2の発現の変化を蛍光免疫染色により検討した.その結果,肝細胞毛細胆管側膜上にmrp2蛋白のdown-regulationが観察された.mrp1は僅かに肝細胞質内に認められたが,BDLにより毛細胆管側膜及び外側膜に発現が認められた
• Distribution and intracellular localization of multidrug resistance-associated proteins 1 (mrp1) and 2 (mrp2) in rat liver and kidney after bile duct ligation

  Q. L. Pei; Y. Kobayashi; Y. Tanaka; Y. Taguchi; K. Higuchi; M. Kaito; Y. Adachi; N. Ma; R. Semba; T. Kamisako

  Japanese Pharmacology and Therapeutics 29 SUPPL. 1 2001年 

  The liver and kidney play a major role in the elimination of a wide variety of endo-xenobiotic anionic substrates into bile and urine. They are mediated by adenosine triphosphate (ATP)-dependent conjugate export pumps, multidrug resistance-associated proteins. In this report, chronological regulations and localization of mrp1 and mrp2 in rat liver and kidney during bile duct ligation were exanimated using immunoflurescence staining. BDL induced down-regulation and fuzzy pericanalicular localization of mrp2 in rat liver. This change was accompanied by the corresponding increase in hepatorenal mrp1, increase in renal mrp2. Reciprocal changes of these transporters in liver and kidney are probably the results of an adaptation to impaired hepatic excretion of conjugated organic anions.
• Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance

  T Kamisako; Y Kobayashi; K Takeuchi; T Ishihara; K Higuchi; Y Tanaka; EC Gabazza; Y Adachi

  JOURNAL OF GASTROENTEROLOGY 35 9 659 - 664 2000年09月 

  Bilirubin is taken up from blood into hepatocytes by sinosuidal membrane transporters and then excreted into bile through the bile canalicular membrane mainly as bilirubin glucuronides. (1) Mechanism of bilirubin uptake into hepatocytes: many organic anions are incorporated into hepatocytes by organic anion transporting polypeptides (rat, oatp 1, oatp2. oatp3 human, OATP), liver-specific transporter (r1st/HLST), and/or by organic anion transporters (OAT2, OAT3). Oatp1 and HLST transport bilirubin monoglucuronide. However, a transporter of unconjugated bilirubin in the sinusoidal membrane has not as yet been identified. Unconjugated bilirubin may also go across the hepatocyte sinusoidal membrane by a diffusion process. (2) Intrahepatic transport and conjugation of bilirubin: ligandin carries bilirubin to the endoplasmic reticulum (ER) of hepatocytes. In the ER, bilirubin is conjugated by bilirubin uridine diphosphate (UDP)-glycosyltransferase (bilirubin UGT; UGT1A1) to form mono- and diglucuronides of bilirubin. (3) Transport mechanism of bilirubin glucuronides across the hepatocyte canalicular membrane: at the canalicular membrane, bilirubin glucuronides are excreted into bile by multidrug resistance-associated protein 2 (MRP2), a member of the ATP-binding cassette transporter family. (4) Regurgitation of bilirubin glucuronides into blood: MRP3, which is located in the lateral membrane, transports bilirubin glucuronides into blood under conditions of impaired biliary bilirubin excretion.
• 急速に進行した性器結核を伴う結核性腹膜炎の１例

  田中 裕滋; 後藤 浩之; 牧田 慶久; 小林 由直; 越山 肇; 千田 豊; 木村 光政; 島地 泰敏; 足立 幸彦

  日本内科学会雑誌 88 7 1326 - 1328 The Japanese Society of Internal Medicine 1999年 

  症例は23歳,未婚女性.持続する高熱で当科へ入院し,抗生物質投与で改善せず,婦人科を受診し,卵巣嚢腫破裂が疑われ,緊急開腹術が施行された.大網の生検で結核性腹膜炎と診断され,抗結核療法にて軽快した.合併していた結核性卵管留腫は一時増大したが,治療開始三カ月で消失した.結核性腹膜炎は通常緩徐な経過を辿るが,本症例では進行が急速であり試験開腹に到った.急速に進行する腹膜炎の原因としても結核は留意すべきと考え報告した.

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  田中裕滋; 上硲俊法

  第75回日本栄養・食糧学会大会 2021年07月
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  田中 裕滋; 池田 高紀; 小川 博; 上硲 俊法

  第74回日本栄養・食糧学会大会 2020年05月 口頭発表（一般）
• Adaptive regulation of bile acid and cholesterol transporters in mouse kidney and intestine during alpha-naphthylisothiocyanate (ANIT)-induced cholestasis  [通常講演]

  田中 裕滋; 池田 高紀; 小川 博; 上硲 俊法

  The59th Annual Meeting of the Society of toxicology(SOT) 2020年03月 ポスター発表
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  田中 裕滋; 池田 高紀; 小川 博; 上硲 俊法

  AASLD Annual Meeting 2019年11月 ポスター発表
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  田中 裕滋; 上硲 俊法

  第55回日本肝臓学会総会 2019年05月 口頭発表（一般）
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  田中 裕滋; 池田 高紀; 小川 博; 上硲 俊法

  第73回日本栄養・食糧学会大会 2019年05月 口頭発表（一般）
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  田中 裕滋; 池田 高紀; 小川 博; 上硲 俊法

  The58th Annual Meeting of the Society of toxicology(SOT) 2019年03月 ポスター発表
• 魚油含有食摂取がマウスの脂質・胆汁酸代謝に及ぼす影響  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第72回日本栄養・食糧学会大会 2018年05月 口頭発表（一般）
• Gender-divergent expression of lipid and bile acid metabolism related genes in adult mice offspring of dams fed a long-term high-fat diet before and during pregnancy and lactation  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  AASLD Annual Meeting 2016年11月 ポスター発表
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  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第55回日本栄養・食糧学会近畿支部大会 2016年10月 口頭発表（一般）
• コレステロールとジオスゲニンの同時摂取がコレステロールおよび胆汁酸代謝に及ぼす影響  [通常講演]

  田中 裕滋; 上硲 俊法

  第51回日本肝臓学会総会 2015年05月 口頭発表（一般）
• Ezetimibe prevents diosgenin-induced cholestatic liver injury in mice  [通常講演]

  田中 裕滋; 上硲 俊法

  AASLD Annual Meeting 2014年10月 ポスター発表
• ワサビ由来6-メチルスルフィニルへキシルイソチオシアネートはマウスの高脂肪食誘発性脂肪肝をNrf2依存性に改善する  [通常講演]

  田中 裕滋; 池田 高紀; 山本和夫; 小川 博; 上硲 俊法

  第50回日本肝臓学会総会 2014年05月 口頭発表（一般）
• エゼチミブ投薬によるジオスゲニン誘発胆汁鬱滞性肝障害の抑制効果  [通常講演]

  田中 裕滋; 池田 高紀; 山本和夫; 小川 博; 上硲 俊法

  第50回日本肝臓学会総会 2014年05月 口頭発表（一般）
• 高脂肪食摂取マウスにおけるエゼチミブ投薬による肝内鉄値増加  [通常講演]

  田中 裕滋; 岸野 好純; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第49回日本肝臓学会総会 2013年06月 東京 第49回日本肝臓学会総会
  
• ワークショップ：胆汁酸研究の最近の進歩 高脂肪食摂取Nrf2欠損マウスにおけるオルチプラズによる肝障害の改善効果  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第49回日本肝臓学会総会 2013年06月 東京 第49回日本肝臓学会総会
  
• Wasabi derivative 6-methylsulfinyl-hexyl, a potent Nrf2 activator, prevents the fatty liver produced by a high-fat diet but does not attenuate hepatic iron overload in mice  [通常講演]

  田中 裕滋; 上硲 俊法

  AASLD Annual Meeting 2013年 ポスター発表
• The Nrf2 activator oltipraz alters cholesterol and bile acid metabolism related genes expression via Nrf2-dependent and independent signal in mice fed a high-fat diet.  [通常講演]

  田中 裕滋; 上硲 俊法

  AASLD Annual Meeting 2012年11月 Boston AASLD Annual Meeting
  
• 雄性OLETF ラットにおけるペルーハーブエキス末の腸内環境改善作用  [通常講演]

  池田 高紀; 田中 裕滋; 森井 浩子; 上硲 俊法; 小川 博

  第51回日本栄養・食糧学会近畿支部大会 2012年10月 兵庫県 第51回日本栄養・食糧学会近畿支部大会
  
• Nrf2activatorであるoltiprazはNrf2非依存性に脂質・胆汁酸代謝に影響を及ぼす  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第48回日本肝臓学会総会 2012年06月 金沢 第48回日本肝臓学会総会
  
• Nrf2欠損マウスにおける高脂肪食摂取下での血清ならびに肝臓脂質動態  [通常講演]

  池田 高紀; 田中 裕滋; 上硲 俊法; 小川 博

  第50回日本栄養・食糧学会近畿支部大会 2011年11月 大阪狭山市 第50回日本栄養・食糧学会近畿支部大会
  
• ワークショップ２：NASH－我が国の実態と発生機序の解明に向けて Nrf2欠損マウスにおける鉄代謝および脂質代謝の調節不全  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第47回日本肝臓学会総会 2011年06月 東京 第47回日本肝臓学会総会
  
• ラットにおけるパスチャカエキス末の長期間摂取による安全性と有効作用の検討  [通常講演]

  高橋 勝美; 池田 高紀; 井藤 美咲; 森井 浩子; 田中 裕滋; 上硲 俊法; 小川 博

  第65回日本栄養・食糧学会大会 2011年05月 東京 第65回日本栄養・食糧学会大会
  
• Dysregulation of hepcidin and lipid metabolism-related genes in the liver of Nrf2-null mice.  [通常講演]

  田中 裕滋; 上硲 俊法

  AASLD Annual Meeting 2011年 San Francisco AASLD Annual Meeting
  
• Dietary fish oil up-regulates gene expression of cholesterol and bile acid metabolism in mouse liver and intestine.  [通常講演]

  田中 裕滋; 上硲 俊法

  2010 AASLD Annual Meeting 2010年10月 Boston 2010 AASLD Annual Meeting
  
• クレアチニンクリアランスの検査制度向上を目的とした検査指導の有用性  [通常講演]

  米本 圭佑; 井本 真由美; 森嶋 祥之; 内藤 昭智; 今野 元博; 田中 裕滋; 上硲 俊法

  第57回日本臨床検査医学会学術集会 2010年09月 東京 第５７回日本臨床検査医学会学術集会
  
• 脂肪酸組成の異なる食事の肝臓および小腸の脂質・胆汁酸代謝関連遺伝子への影響  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第46回日本肝臓学会総会 2010年05月 山形市 第４６回日本肝臓学会総会
  
• 脂肪酸組成の異なる高脂肪食負荷マウスにおける腸肝循環関連遺伝子発現の変動-大豆油とラードとの比較  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第45回日本肝臓学会総会 2009年06月 神戸 第４５回日本肝臓学会総会
  
• カルコンパウダーの脂質代謝改善作用―容量と作用機序の検討  [通常講演]

  池田 高紀; 田中 裕滋; 上硲 俊法; 小川 博

  第63回日本栄養・食糧学会大会 2009年05月 長崎 第63回日本栄養・食糧学会大会
  
• 高脂肪食摂取がマウスの脂質および胆汁酸代謝に及ぼす影響-大豆油とラードの比較  [通常講演]

  田中 裕滋; 池田 高紀; 山本 和夫; 小川 博; 上硲 俊法

  第63回日本栄養・食糧学会大会 2009年05月 長崎 第63回日本栄養・食糧学会大会
  
• DanazolがEstradiol免疫測定法に及ぼす影響  [通常講演]

  岸野 好純; 内藤 昭智; 田中 裕滋; 上硲 俊法

  第55回日本臨床検査医学会学術集会 2008年11月 名古屋 第５５回日本臨床検査医学会学術集会
  
• カルコンパウダーの脂質代謝改善作用ー用量の検討  [通常講演]

  池田 高紀; 田中 裕滋; 上硲 俊法; 小川 博

  2008年10月 第47回日本栄養・食糧学会近畿支部大会（奈良）
• 高脂肪食負荷マウスにおける抗酸化酵素制御転写因子NF-E2-related factor 2 (Nrf2)の肝内遊離脂肪酸と酸化ストレスの阻害  [通常講演]

  田中 裕滋; 上硲 俊法; Klaassen CD

  2008年06月 第４４回日本肝臓学会総会（松山）
• Nuclear factor E2 p45-related factor(Nrf2) promotes liver injury in mice after bile-duct ligation.  [通常講演]

  Tanaka Y; Slitt AL; Klaassen CD; Copple BL

  AASLD Annual Meeting 2006年10月 ポスター発表
• Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via nf-e2-related factor 2 in rats and mice.  [通常講演]

  Tanaka Y; Maher JM; Chen C; Klaassen CD

  The45th Annual Meeting of the Society of toxicology(SOT) 2006年03月 ポスター発表
• Kupffer cell-mediated downregulationof heaptic transporter expression in rat hepatic ischemia-reperfusion.  [通常講演]

  Tanaka Y; Chen C; Maher JM; Klaassen CD

  The 13th North American International Society for the Study of Xenobiotics(ISSX) 2005年10月 ポスター発表
• Tissue distribution and hormonal regulation of the breast cancer resistance protein (BCRP/ABCG2) in rats and mice.  [通常講演]

  Tanaka Y; Slitt AL; Leazer T; Maher JM; Klaassen CD

  The 43th Annual Meeting of the Society of toxicology(SOT) 2004年03月 ポスター発表

MISC

• Gender-divergent expression of lipid and bile acid metabolism related genes in adult mice offspring of dams fed a long-term high-fat diet before and during pregnancy and lactation

  Yuji Tanaka; Takanori Ikeda; Kazuo Yamamoto; Hiroshi Ogawa; Toshinori Kamisako HEPATOLOGY 64 157A -158A 2016年10月
• Ezetimibe prevents diosgenin-induced cholestatic liver injury in mice

  Yuji Tanaka; Toshinori Kamisako HEPATOLOGY 60 406A -407A 2014年
• Wasabi derivative 6-methylsulfinylhexyl isothiocyanate, a potent Nrf2 activator, prevents the fatty liver produced by a high-fat diet but did not attenuate hepatic iron overload in mice

  Yuji Tanaka; Toshinori Kamisako HEPATOLOGY 58 554A -555A 2013年10月
• The Nrf2 activator oltipraz alters cholesterol and bile acid metabolism related genes expression via Nrf2-dependent and independent signaling in mice fed a high-fat diet

  Yuji Tanaka; Toshinori Kamisako HEPATOLOGY 56 540A -541A 2012年10月
• DYSREGULATION OF HEPCIDIN AND LIPID METABOLISM-RELATED GENE EXPRESSION IN LIVERS OF NRF2-NULL MICE

  Yuji Tanaka; Toshinori Kamisako HEPATOLOGY 54 1165A -1166A 2011年10月
• DIETARY FISH OIL UP-REGULATES GENE EXPRESSION OF CHOLESTEROL AND BILE ACID METABOLISM IN MOUSE LIVER AND INTESTINE

  Yuji Tanaka; Toshinori Kamisako HEPATOLOGY 52 (4) 934A -934A 2010年10月
• 司会のことば

  田中 裕滋; 森嶋 祥之; 上硲 俊法 臨床病理 57 (11) 1064 -1065 2009年11月
• THE NRF2-KEAP1 SIGNALING PATHWAY IS ACTIVATED IN MICE DURING THE DEVELOPMENT OF NONALCOHOLIC STEATOHEPATITIS

  Yu-Kun J. Zhang; Ronnie L. Yeager; Yuji Tanaka; Curtis D. Klaassen HEPATOLOGY 50 (4) 1181A -1181A 2009年10月
• BILE ACIDS IN NEWBORNS INITIATE THE EXPRESSION OF MAJOR HEPATIC TRANSPORTERS INVOLVED IN ENTEROHEPATIC CIRCULATION

  Yue Cui; Lauren M. Aleksunes; Yuji Tanaka; Curtis D. Klaassen HEPATOLOGY 48 (4) 1038A -1038A 2008年10月
• Nuclear factor E2 p45-related factor 2 (Nrf2) promotes liver injury in mice after bile-duct ligation

  Yuji Tanaka; Angela L. Slitt; Curtis D. Klaassen; Bryan L. Copple HEPATOLOGY 44 (4) 605A -605A 2006年10月
• Expressions of hepatobiliary organic anion transporters and bilirubin-conjugating enzyme in differentiating embryonic stem cells

  Y Tanaka; M Yoshikawa; Y Kobayashi; M Kuroda; M Kaito; A Shiroi; J Yamao; H Fukui; S Ishizaka; Y Adachi BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 309 (2) 324 -330 2003年09月
• 日本人におけるbilirubin UDP-glucuronosyltranseferase gene(UGT1A1)genotypeに関する検討

  竹内 圭介; 玉置 繁憲; 山本 美香; 荒木 潤; 三藤 留美; 田中 秀明; 堀池 眞一郎; 井谷 俊夫; 竹尾 雅樹; 黒田 誠; 田中 裕滋; 藤田 尚己; 岩佐 元雄; 小林 由直; 生駒 次朗; 垣内 雅彦; 渡辺 省三; 足立 幸彦 肝臓 44 (Suppl.1) A157 -A157 2003年04月
• C型慢性肝炎患者白血球中8-OHdG測定の臨床的有用性の検討

  堀池 眞一郎; 垣内 雅彦; 荒木 潤; 三藤 留美; 山本 実香; 田中 秀明; 井谷 俊夫; 竹尾 雅樹; 黒田 誠; 田中 裕滋; 竹内 圭介; 小林 由直; 岩佐 元雄; 玉置 繁憲; 生駒 次朗; 渡辺 省三; 足立 幸彦 肝臓 44 (Suppl.1) A271 -A271 2003年04月
• bilirubin UDP-glucuronosyltransferase(UGT1A1)遺伝子解析にて新しいgenotypeを認めたGilbert症候群患者の2症例

  竹内 圭介; 玉置 繁憲; 田中 秀明; 井谷 俊夫; 竹尾 雅樹; 黒田 誠; 田中 裕滋; 藤田 尚己; 小林 由直; 岩佐 元雄; 生駒 次朗; 垣内 雅彦; 渡辺 省三; 佐藤 浩; 足立 幸彦 肝臓 43 (Suppl.2) A404 -A404 2002年09月
• Different HCV dynamics between the free virions and immune complexes in serum of patients with chronic hepatitis C with sustained interferon response

  N Fujita; M Kaito; M Takeo; M Kuroda; Y Tanaka; K Higuchi; K Takeuchi; Y Kobayashi; M Iwasa; J Ikoma; Y Adachi; S Watanabe GASTROENTEROLOGY 123 (1) 76 -76 2002年07月
• Interferon投与時における血中HCV dynamicsの検討 free virionとimmune complexの差異

  藤田 尚己; 垣内 雅彦; 竹尾 雅樹; 黒田 誠; 田中 裕滋; 樋口 国博; 竹内 圭介; 小林 由直; 岩佐 元雄; 生駒 次朗 肝臓 43 (Suppl.1) A77 -A77 2002年05月
• Statistical Parametric Mappingを用いた肝硬変症の局所脳血流異常の検討

  岩佐 元雄; 渡辺 ゆり; 垣内 雅彦; 松村 要; 竹尾 雅樹; 黒田 誠; 樋口 国博; 田中 裕滋; 竹内 圭介; 藤田 尚己 肝臓 43 (Suppl.1) A60 -A60 2002年05月
• ヒト肝及び腎近位尿細管培養細胞におけるビリルビン及び胆汁酸のMultidrug Resistance-associated Protein 2(MRP2)発現に及ぼす影響

  田中 裕滋; 小林 由直; 樋口 国博; 黒田 誠; 竹内 圭介; 岩佐 元雄; 上硲 俊法; 足立 幸彦 肝臓 43 (Suppl.1) A196 -A196 2002年05月
• 胃癌根治術後に難治性腹水を来した肝リンパ漏の一例

  末松 三奈; 田中 裕滋; 田口 由紀子; 竹尾 雅樹; 黒田 誠; 樋口 国博; 竹内 圭介; 藤田 尚己; 小林 由直; 岩佐 元雄; 生駒 次朗; 垣内 雅彦; 足立 幸彦; 井本 一郎; 大北 喜基; 大森 教成 日本消化器病学会雑誌 99 (臨増総会) A305 -A305 2002年03月
• 日本人におけるUGT1A1の遺伝子多型

  竹内 圭介; 石原 知明; 樋口 国博; 田中 裕滋; 藤田 尚己; 岩佐 元雄; 小林 由直; 玉置 繁憲; 生駒 次朗; 垣内 雅彦 日本臨床分子医学会記録 38 50 -50 2002年02月
• C型慢性肝炎に対するインターフェロン・サイクロスポリンA併用療法の検討

  垣内 雅彦; 竹尾 雅樹; 黒田 誠; 樋口 国博; 田中 裕滋; 竹内 圭介; 藤田 尚己; 岩佐 元雄; 小林 由直; 生駒 次朗 肝臓 42 (Suppl.3) A498 -A498 2001年11月
• IFN無効C型慢性肝炎患者例に対するUDCA治療と鉄摂取制限食の併用効果について

  竹尾 雅樹; 生駒 次朗; 樋口 国博; 田中 裕滋; 竹内 圭介; 小林 由直; 岩佐 元雄; 垣内 雅彦; 渡邊 省三; 足立 幸彦 肝臓 42 (Suppl.3) A500 -A500 2001年11月
• AFP,AFP-L3分画,PIVKA-II測定の肝細胞癌診断における有用性

  生駒 次朗; 竹尾 雅樹; 黒田 誠; 樋口 国博; 田中 裕滋; 竹内 圭介; 藤田 尚己; 岩佐 元雄; 小林 由直; 垣内 雅彦 肝臓 42 (Suppl.3) A529 -A529 2001年11月
• Cerebral blood flow in basal ganglia is correlated with clinical signs of hepatic encephalopathy in patients with liver cirrhosis.

  M Iwasa; M Kaito; K Matsumura; Y Watanabe; J Ikoma; Y Kobayashi; Y Tanaka; M Takeo; K Takeda; Y Adachi HEPATOLOGY 34 (4) 551A -551A 2001年10月
• びまん性肝疾患の画像診断 脳血流SPECTを用いた肝硬変症の大脳基底核血流量の検討

  岩佐 元雄; 渡辺 ゆり; 松村 要; 樋口 国博; 田中 裕滋; 竹内 圭介; 藤田 尚己; 小林 由直; 生駒 次朗; 垣内 雅彦 肝臓 42 (Suppl.1) A38 -A38 2001年05月
• 肝硬変患者のHealth Related QOLの検討

  岩佐 元雄; 垣内 雅彦; 生駒 次朗; 樋口 国博; 田中 裕滋; 竹内 圭介; 藤田 尚己; 小林 由直; 渡辺 省三; 足立 幸彦 肝臓 42 (Suppl.1) A302 -A302 2001年05月
• 閉塞性黄疸モデルラットにおけるmrp2蛋白の肝及び腎における細胞内分布と腎におけるビリルビン輸送機能の検討

  田中 裕滋; 小林 由直; 樋口 国博; Pei Qiu-Ling; 竹内 圭介; 黒田 誠; 岩佐 元雄; 生駒 次朗; 垣内 雅彦; 上硲 俊法 肝臓 42 (Suppl.1) A240 -A240 2001年05月
• 【肝病態生理研究のあゆみ】日本人におけるBilirubin UDP-glucuronosyltranseferase gene(UGT1A1)変異

  竹内 圭介; 石原 知明; 樋口 国博; 田中 裕滋; 藤田 尚己; 岩佐 元雄; 玉置 繁憲; 生駒 次朗; 垣内 雅彦; 足立 幸彦 薬理と治療 29 (Suppl.1) S89 -S91 2001年04月
• Improvement of serum aminotransferase levels with dietary iron reduction in patients with chronic hepatitis C.

  M Iwasa; M Kaito; J Ikoma; Y Kobayashi; N Fujita; Y Tanaka; K Higuchi; S Watanabe; Y Adachi HEPATOLOGY 32 (4) 564A -564A 2000年10月
• MRP2/cMOAT is down-regulated in hepatocytes but upregulated in renal epithelial cells in bile duct-ligated rats.

  Y Kobayashi; K Higuchi; Y Tanaka; PQ Ling; T Kamisako; K Takeuchi; T Ishihara; M Iwasa; M Kaito; Y Adachi HEPATOLOGY 32 (4) 429A -429A 2000年10月
• Clinical significance of serum levels of non-immune complexed hepatitis C virus in patients with chronic hepatitis C: Correlation with genotype and response to IFN therapy.

  N Fujita; M Kaito; Y Tanaka; K Higuchi; K Takeuchi; T Ishihara; M Iwasa; Y Kobayashi; J Ikoma; Y Adachi; S Watanabe HEPATOLOGY 32 (4) 288A -288A 2000年10月
• Dubin-Johnson(D-J)類似顆粒を認めた黒色肝の1例

  石原 知明; 垣内 雅彦; 竹内 圭介; 樋口 国博; 田中 裕滋; 小林 由直; 岩佐 元雄; 生駒 次朗; 渡辺 省三; 梶原 進 肝臓 41 (Suppl.3) A552 -A552 2000年10月
• 日本人におけるbilirubin UDP-glycosyltranseferase gene(UGT1A1)のpolymorphism

  竹内 圭介; 石原 知明; 樋口 国博; 田中 裕滋; 藤田 尚己; 岩佐 元雄; 小林 由直; 玉置 繁憲; 生駒 次朗; 垣内 雅彦 肝臓 41 (Suppl.2) A409 -A409 2000年09月
• C型慢性肝炎に対するインターフェロン・サイクロスポリンA併用療法におけるヘルパーT細胞機能

  生駒 次朗; 垣内 雅彦; 樋口 国博; 田中 裕滋; 竹内 圭介; 石原 知明; 中川 直樹; 藤田 尚己; 岩佐 元雄; 小林 由直 肝臓 41 (Suppl.2) A399 -A399 2000年09月
• C型慢性肝炎に対する鉄摂取制限の効果

  岩佐 元雄; 垣内 雅彦; 樋口 国博; 田中 裕滋; 竹内 圭介; 石原 知明; 中川 直樹; 藤田 尚己; 小林 由直; 生駒 次朗 肝臓 41 (Suppl.2) A400 -A400 2000年09月
• 閉塞性黄疸モデルラットにおけるmultidrug resistance-associated protein 2(mrp 2)発現の肝腎相関

  田中 裕滋; 小林 由直; 樋口 国博; 斐 秋玲; 竹内 圭介; 石原 知明; 岩佐 元雄; 生駒 次朗; 垣内 雅彦; 上硲 俊法 肝臓 41 (Suppl.2) A414 -A414 2000年09月
• 患者血液中における免疫グロブリン非結合性HCV量の臨床的意義

  藤田 尚己; 垣内 雅彦; 樋口 国博; 田中 裕滋; 竹内 圭介; 石原 知明; 中川 直樹; 岩佐 元雄; 小林 由直; 生駒 次朗 肝臓 41 (Suppl.1) A270 -A270 2000年05月
• 小腸内視鏡検査にて術前診断しえた肺癌よりの転移性小腸腫瘍の1例

  田中 裕滋; 木村 光政; 小林 由直; 牧田 慶久; 吉田 康史; 山口 道彦; 越山 肇; 足立 幸彦 日本消化器内視鏡学会雑誌 = Gastroenterological endoscopy 42 (2) 169 -174 2000年02月
• 薬剤性肝障害の臨床的検討

  岩佐 元雄; 垣内 雅彦; 樋口 国博; 田中 裕滋; 竹内 圭介; 小林 由直; 生駒 次朗; 渡辺 省三; 足立 幸彦 肝臓 40 (Suppl.3) 79 -79 1999年10月

受賞

• 2020年 近畿大学医学部 2018年度 Best Teacher賞
  
• 2019年 日本栄養・食糧学会 トピックス演題
  
• 2012年 米国肝臓学会 優秀演題賞
  
• 2006年 米国毒性学会 最優秀演題賞
  

共同研究・競争的資金等の研究課題

• 植物ステロールの効能と毒性における小腸コレステロール排泄機構の役割

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2021年04月 -2024年03月 

  代表者 : 田中 裕滋

   

  植物ステロールにはコレステロール(CHOL)低下作用があることが知られている。一方で過剰になると動脈硬化や胆汁鬱滞性肝障害など生体への毒性が認められる。しかしながら、これらの効能や毒性に対する小腸の役割は十分に解明されていない。近年、血中コレステロールの排泄経路として肝臓から胆管を介した経路だけでなく、新規の排泄経路として腸管に直接排泄する経路であるTICE(trans-intestinal cholesterol efflux)が発見された。そこで、2021年度は食餌中の植物ステロールの含量の異なる油脂を摂取させたラットにおいてSham手術と総胆管結紮(BDL)術を施行し、肝臓から胆汁中へ植物ステロールを排泄するルートを遮断することでTICEに如何なる影響を及ぼすか観察するため以下の研究を行った。方法と結果：6週令雄性ラットにAIN-93に準拠して作成した以下の4群の食餌を摂取させた。1)10%大豆油(S群) 2)10%大豆油+0.005%エゼチミブ(S+E群) 3)10%魚油(F群) 4)10%魚油+0.005%エゼチミブ(F+E群)。各々の飼料で4週(10週令)飼育した後にSham術とBDLを施行し72時間後に実験に供した。BDLにより①血清CHOLの上昇を認め、②TICEを反映する糞中CHOLはS群とF+E群で増加したがS+E群とF群では増加しなかった。③肝Abca1はS群で増加したがS+E群とF群では増加しなかった。④小腸Abcg5とAbcg8はS群で増加したがエゼチミブ添加によりAbcg8の誘導は抑制された。一方、魚油群では誘導は認められなかった。また、TICEに関連している可能性があるLDLレセプターやSR-B1では差は認められなかった。これらの結果からBDL下では大豆油に含まれる毒性物質の蓄積から生体を防御するためにTICEが増強している可能性が示唆された。
• 食餌中の脂質組成が小腸からのコレステロール排泄に及ぼす影響

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2018年04月 -2021年03月 

  代表者 : 上硲 俊法; 田中 裕滋

   

  小腸はコレステロール(CH)を吸収するのみならず血中から直接小腸管腔にコレステロールを排泄している経路（TICE) の存在が明らかとなった。前年度の研究においてω３脂肪酸含有の多い魚油をマウスに摂取させると小腸のステロールの排泄に関与するABCG5/G8の発現が増加し、便中のステロール排泄が増加している事を確認した。このことは魚油による血中CH低下作用にTICEが関与している可能性を示唆する。ただし便中ステロールはTICEとCH吸収のバランスにより制御されているため、2019年度にはCHの吸収コンポーネントをブロックするezetimibeを併用する事により糞便中ステロール排泄に如何なる影響を及ぼすかを解明する事を課題と以下の実験を行う事にした。（方法）６週令雄性SDラットを標準飼料（AIN-93）に準拠して作成した大豆油投与群（C群）、魚油投与群（F群）、ezetimibe(E)を添加群（E群）と魚油＋E投与群（FE群）を作成した。各々の飼料で4週（10週令）飼育した後に実験に供した。肝臓の各種脂質、糞便コレステロールを測定し、肝臓および小腸の脂質代謝関連mRNAの発現を定量した。（結果）①肝臓の中性脂肪(TG)とCH含量は、F群、E群では有意な変化はみなかったが、FE群ではTG, TCとも著減していた。TICEを反映する糞便中CHは、F群、E群では各々1.42倍、1.28倍であったがFE群ではC群と差を認めなかった。小腸の脂質代謝関連mRNAの発現はF群、E群ともCH排泄に関わるAbcG5やAbcG8の発現の増加をみた。過去の報告においてTICEに関連がある可能性が示唆されていたLDL-RやSR-B1の発現量に差は見られなかった。（結論）FE群においては肝臓の脂質が著減していたがTICEの影響は乏しいと考えられた。
• 胆汁鬱滞による脂質代謝異常に対する小腸の役割の解明

  日本学術振興会: 科学研究費補助金・基礎研究 (C)：

  研究期間 : 2018年04月 -2021年03月 

  代表者 : 田中裕滋
• 胎生期から成長期の栄養環境が脂質吸収に及ぼす影響

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2015年04月 -2018年03月 

  代表者 : 上硲 俊法; 田中 裕滋

   

  食餌中の脂質含量や質を変化させると肝臓のみならず小腸においても脂質代謝・吸収に関与する遺伝子産物の発現が変化している。また胎児期に暴露された栄養環境がいくつかの代謝関連遺伝子をエピジェネティックス制御している事が知られている。そこで本研究においては、胎児期から成長期にかけての脂肪組成の違う栄養環境が脂質代謝や胆汁酸代謝にいかなる影響を引き起こすかを検討した。母親世代の脂質摂取の差は、雌F1世代の肝脂質・胆汁酸代謝に関して遺伝子産物発現量に影響を及ぼし雄ではこの変化は乏しかった。一方、小腸ではこれらの遺伝子産物発現に差は認められず、胎児期の栄養環境の差は脂質吸収に影響を及ぼさなかった。
• 脂質代謝と酸化ストレス制御間のクロストーク機構に及ぼす食餌中脂質組成の役割

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  研究期間 : 2012年04月 -2015年03月 

  代表者 : 上硲 俊法; 田中 裕滋

   

  Nrf2系による酸化ストレス制御と脂質代謝のクロストークを検討した。①食餌中脂質の質的差異は脂肪酸分解、コレステロール排泄、コレステロール(CH)異化にNrf2系を介し影響した。②CH吸収とNrf2系の関係を検討し、CH吸収量の変化はLXRαの標的遺伝子である脂肪酸代謝関連遺伝子、CHトランスポーター、胆汁酸合成酵素を制御しており、Nrf2はLXRαを介した脂質代謝制御に関与している事を見出した。③Nrf2アクチベーターの１つ6-methylsulfinylhexylisothianate(6-MSITC) はNrf2依存性に肝への脂肪沈着とサイトカイン産生を抑制している事を明らかとした。
• 酸化ストレス制御転写因子を標的とした脂肪肝炎の発症機構の 解明と食品成分による予防

  日本学術振興会：科学研究費補助金・基盤研究 (C)

  研究期間 : 2011年04月 -2014年03月 

  代表者 : 田中裕滋

委員歴

• 2016年04月 - 現在   日本臨床検査医学会   医療安全委員

担当経験のある科目

基礎医学帝塚山学院大学
臨床検査医学近畿大学

その他のリンク

researchmap

https://researchmap.jp/ytanakanrf2