Updated on 2024/09/20

写真a

 
YAGAI Tomoki
 
Organization
Research Institute of Environmental Medicine Division of Stress Recognition and Response Designated lecturer
Title
Designated lecturer

Research Areas 2

  1. Life Science / Molecular biology

  2. Life Science / Pathological biochemistry

Research History 5

  1. Nagoya University   Research Institute of Environmental Medicine   Associate Professor/Lecturer

    2023.1

  2. Tohoku University   Institute of Development, Aging and Cancer   Assistant Professor

    2019.10 - 2022.12

  3. 日本学術振興会海外特別研究員(NIH)

    2017.1 - 2018.12

  4. National Institutes of Health, National Cancer Institute   Laboratory of Metabolism   Postdoctoral Fellow

    2014.10 - 2019.9

  5. The University of Tokyo   Institute of Molecular and Cellular Biosciences   Project Researcher

    2014.4 - 2014.9

Education 1

  1. University of Tokyo   Graduate School of Science

    2009.4 - 2014.3

Awards 6

  1. 第40回東北大学加齢医学研究所集談会コンテスト 準優勝

    2022.3  

    谷貝 知樹

  2. 第36回東北大学加齢医学研究所集談会コンテスト 優勝

    2020.1  

    谷貝 知樹

  3. Fellows Award for Research Excellence 2019

    2018   National Institutes of Health  

    Tomoki Yagai

  4. ポスター賞

    2013.6   第13回東京大学生命科学シンポジウム  

    谷貝 知樹

  5. 鈴木紘一メモリアル賞

    2012.12   第85回日本生化学会大会  

    谷貝 知樹

  6. 第14回東京大学分子細胞生物学研究所所内発表会 優秀賞第二位

    2012.11  

    谷貝 知樹

▼display all

 

Papers 19

  1. 今月の特集 肥満と健康障害 肥満と健康障害 非アルコール性脂肪性肝疾患(NAFLD)

    谷貝 知樹, 菅波 孝祥

    臨床検査   Vol. 68 ( 5 ) page: 614 - 618   2024.5

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    Authorship:Lead author, Corresponding author   Publisher:株式会社医学書院  

    DOI: 10.11477/mf.1542203619

  2. Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor. Reviewed International journal

    Tomoki Yagai, Takahisa Nakamura

    Frontiers in medicine   Vol. 9   page: 1060244 - 1060244   2022.11

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.

    DOI: 10.3389/fmed.2022.1060244

    PubMed

  3. Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation. Reviewed International journal

    Daisuke Aibara, Shogo Takahashi, Tomoki Yagai, Donghwan Kim, Chad N Brocker, Moshe Levi, Kimihiko Matsusue, Frank J Gonzalez

    iScience   Vol. 25 ( 5 ) page: 104196 - 104196   2022.5

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    Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation.

    DOI: 10.1016/j.isci.2022.104196

    PubMed

  4. YAP-TEAD mediates PPAR α-induced hepatomegaly and liver regeneration in mice. Reviewed International journal

    Shicheng Fan, Yue Gao, Aijuan Qu, Yiming Jiang, Hua Li, Guomin Xie, Xinpeng Yao, Xiao Yang, Shuguang Zhu, Tomoki Yagai, Jianing Tian, Ruimin Wang, Frank J Gonzalez, Min Huang, Huichang Bi

    Hepatology (Baltimore, Md.)   Vol. 75 ( 1 ) page: 74 - 88   2022.1

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    BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. APPROACH AND RESULTS: In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. CONCLUSIONS: This study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.

    DOI: 10.1002/hep.32105

    PubMed

  5. Feedback repression of PPARα signaling by Let-7 microRNA. Reviewed International journal

    Tomoki Yagai, Tingting Yan, Yuhong Luo, Shogo Takahashi, Daisuke Aibara, Donghwan Kim, Chad N Brocker, Moshe Levi, Hozumi Motohashi, Frank J Gonzalez

    Cell reports   Vol. 36 ( 6 ) page: 109506 - 109506   2021.8

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.

    DOI: 10.1016/j.celrep.2021.109506

    PubMed

  6. FXR-Deoxycholic Acid-TNF-α Axis Modulates Acetaminophen-Induced Hepatotoxicity. Reviewed International journal

    Tingting Yan, Nana Yan, Hong Wang, Tomoki Yagai, Yuhong Luo, Shogo Takahashi, Min Zhao, Kristopher W Krausz, Guangji Wang, Haiping Hao, Frank J Gonzalez

    Toxicological sciences : an official journal of the Society of Toxicology   Vol. 181 ( 2 ) page: 273 - 284   2021.5

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    The idiosyncratic characteristics and severity of acetaminophen (APAP) overdose-induced hepatotoxicity render identifying the predisposing factors and mechanisms of APAP-induced liver toxicity necessary and urgent. Farnesoid X receptor (FXR) controls bile acid homeostasis and modulates the progression of various liver diseases. Although global FXR deficiency in mice enhances APAP intoxication, the mechanism remains elusive. In this study, an increased sensitivity to APAP-induced toxicity was found in global Fxr-null (Fxr-/-) mice, but was not observed in hepatocyte-specific or macrophage-specific Fxr-null mice, suggesting that global FXR deficiency enhances APAP hepatotoxicity via disruption of systematic bile acid homeostasis. Indeed, more bile acid accumulation was found in global Fxr-/- mice, while 2% cholestyramine diet feeding decreased serum bile acids and alleviated APAP hepatotoxicity in global Fxr-/- mice, suggesting that bile acid accumulation contributes to APAP toxicity. Bile acids were suspected to induce macrophage to release tumor necrosis factor-α (TNF-α), which is known to enhance the APAP hepatotoxicity. In vitro, deoxycholic acid (DCA), a secondary bile acid metabolite, significantly induced Tnfa mRNA and dose-dependently enhanced TNF-α release from macrophage, while the same dose of DCA did not directly potentiate APAP toxicity in cultured primary hepatocytes. In vivo, DCA enhanced TNF-α release and potentiated APAP toxicity, both of which were abolished by the specific TNF-α antagonist infliximab. These results reveal an FXR-DCA-TNF-α axis that potentiates APAP hepatotoxicity, which could guide the clinical safe use of APAP.

    DOI: 10.1093/toxsci/kfab027

    PubMed

  7. Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis. Reviewed International journal

    Youbo Zhang, Tingting Yan, Dongxue Sun, Cen Xie, Tianxia Wang, Xiaoyan Liu, Jing Wang, Qiong Wang, Yuhong Luo, Ping Wang, Tomoki Yagai, Kristopher W Krausz, Xiuwei Yang, Frank J Gonzalez

    Free radical biology & medicine   Vol. 148   page: 33 - 41   2020.2

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    Inflammatory bowel disease (IBD) represents a group of chronic relapsing intestinal disorders. Rutaecarpine (RUT), isolated from the Traditional Chinese Medicine (TCM) of Evodia rutaecarpa, was reported to suppress IBD. However, the mechanism by which RUT ameliorates dextran sulfate sodium (DSS)-induced IBD is largely unknown. By use of nuclear factor-erythroid 2-related factor 2 (NRF2) knockout mice, cell-based studies, surface plasmon resonance (SPR), western blotting analysis, and molecular docking studies, the mechanism by which RUT affects DSS-induced colitis was explored. In DSS-treated wild-type mice but not in Nrf2-null mice, RUT significantly improved colitis as revealed by rescued body weight loss, improved histology and inflammation, and induced expression of NRF2 target genes in colon and ileum. Cell-based studies showed that RUT significantly increased the LD50 for hydrogen peroxide (H2O2)-induced cell damage, activated NRF2 nuclear translocation, and suppressed the production of reactive oxygen species in H2O2-treated HCT116 cells, activated NRF2 luciferase reporter activities in HCT116 cells and HepG2 cells, and induced expression of NRF2 target genes in primary intestinal epithelial cells. Molecular docking in silico and SPR assays indicated that RUT interacted with kelch-like ECH-associated protein 1 (KEAP1), and extracellular incubation studies revealed that RUT bound to the KEAP1 kelch domain with a calculated equilibrium dissociation constant Kd of 19.6 μM. In conclusion, these results demonstrate that RUT ameliorates DSS-induced colitis, dependent on NRF2, and could be a potential therapeutic option for IBD patients. Mechanistically, RUT potentiates NRF2 nuclear translocation to upregulate NRF2-mediated antioxidant response by directly inhibiting KEAP1-NRF2 interaction.

    DOI: 10.1016/j.freeradbiomed.2019.12.012

    PubMed

  8. Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha-Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation. Reviewed International journal

    Donghwan Kim, Chad N Brocker, Shogo Takahashi, Tomoki Yagai, Taehyeong Kim, Guomin Xie, Hua Wang, Aijuan Qu, Frank J Gonzalez

    Hepatology (Baltimore, Md.)   Vol. 70 ( 1 ) page: 154 - 167   2019.7

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    Chronic activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes MYC-linked hepatocellular carcinoma (HCC) in mice. Recent studies have shown that MYC can function as an amplifier of transcription where MYC does not act as an "on-off" switch for gene expression but rather accelerates transcription rates at active promoters by stimulating transcript elongation. Considering the possibility that MYC may amplify the expression of PPARA target genes to potentiate cell proliferation and liver cancer, gene expression was analyzed from livers of wild-type and liver-specific Myc knockout (MycΔHep ) mice treated with the PPARA agonist pirinixic acid. A subset of PPARA target genes was amplified in the presence of MYC, including keratin 23 (Krt23). The induction of Krt23 was significantly attenuated in MycΔHep mice and completely abolished in Ppara-null mice. Reporter gene assays and chromatin immunoprecipitation confirmed direct binding of both PPARA and MYC to sites within the Krt23 promoter. Forced expression of KRT23 in primary hepatocytes induced cell cycle-related genes. These data indicate that PPARA activation elevates MYC expression, which in turn potentiates the expression of select PPARA target genes involved in cell proliferation. Finally, KRT23 protein is highly elevated in human HCCs. Conclusion: These results revealed that MYC-mediated transcriptional potentiation of select PPARA target genes, such as Krt23, may remove rate-limiting constraints on hepatocyte growth and proliferation leading to liver cancer.

    DOI: 10.1002/hep.30530

    PubMed

  9. Hepatocyte Peroxisome Proliferator-Activated Receptor α Enhances Liver Regeneration after Partial Hepatectomy in Mice. Reviewed International journal

    Guomin Xie, Shi Yin, Zhenzhen Zhang, Dan Qi, Xia Wang, Donghwan Kim, Tomoki Yagai, Chad N Brocker, Yan Wang, Frank J Gonzalez, Hua Wang, Aijuan Qu

    The American journal of pathology   Vol. 189 ( 2 ) page: 272 - 282   2019.2

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    Peroxisome proliferator-activated receptor α (PPARα) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPARα is also a potent hepatic mitogen. Hepatocyte-specific disruption of PPARα inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPARα in partial hepatectomy (PHx)-induced liver regeneration. Herein, using hepatocyte-specific PPARα-deficient (PparaΔHep) mice, the function of hepatocyte PPARα in PHx-induced liver regeneration was investigated. PPARα protein level and transcriptional activity were increased in the liver after PHx. Compared with the Pparafl/fl mice, PparaΔHep mice exhibited significantly reduced hepatocyte proliferation at 32 hours after PHx. Consistently, reduced Ccnd1 and Pcna mRNA and CYCD1 and proliferating cell nuclear antigen protein were observed at 32 hours after PHx in PparaΔHep mice. Furthermore, PparaΔHep mice showed increased hepatic lipid accumulation and enhanced hepatic triglyceride contents because of impaired hepatic fatty acid β-oxidation when compared with that observed in Pparafl/fl mice. These results indicate that PPARα promotes liver regeneration after PHx, at least partially via regulating the cell cycle and lipid metabolism.

    DOI: 10.1016/j.ajpath.2018.10.009

    PubMed

  10. Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development. Reviewed International journal

    Shogo Takahashi, Naoki Tanaka, Tatsuki Fukami, Cen Xie, Tomoki Yagai, Donghwan Kim, Thomas J Velenosi, Tingting Yan, Kristopher W Krausz, Moshe Levi, Frank J Gonzalez

    Hepatology communications   Vol. 2 ( 12 ) page: 1567 - 1582   2018.12

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    Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down-regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR deficiency in mice results in spontaneous HCC with aging, the contribution of tissue-specific FXR deficiency to hepatocarcinogenesis remains unclear. In this study, the prevalence of hepatic tumors, expression of genes related to tumorigenesis, and serum/liver BA levels were compared among male whole-body Fxr-null, hepatocyte-specific Fxr-null (Fxr ∆Hep), and enterocyte-specific Fxr-null (Fxr ∆IE) mice at the age of 3, 14, and 20 months. More than 90% of 20-month-old whole-body Fxr-null mice had hepatic tumors with enhanced hepatic expression of myelocytomatosis oncogene (Myc) and cyclin-dependent kinase 4 (Cdk4) messenger RNAs (mRNAs) and elevated serum taurocholate (TCA) and tauromuricholate (TMCA) and their respective unconjugated derivatives. The incidence of hepatic tumors was significantly lower in Fxr ∆Hep and Fxr ∆IE mice (20% and 5%, respectively), and the increases in Myc and Cdk4 mRNA or serum BA concentrations were not detected in these mice compared to Fxr floxed [fl]/fl mice; a similar tendency was observed in 14-month-old mice. However, increased hepatic c-Myc protein expression was found only in Fxr-null mice at the age of 3, 14, and 20 months. Treatment with TCA induced Myc expression in Fxr-null cultured primary mouse hepatocytes but not in wild-type (WT) mouse hepatocytes, demonstrating that the combination of hepatocyte FXR disruption with elevated TCA is required for Myc induction and ensuing age-dependent hepatocarcinogenesis in Fxr-null mice. Conclusion: There is a relatively low risk of hepatic tumors by inhibition of FXR in enterocytes, likely due to the lack of increased TCA and Myc induction.

    DOI: 10.1002/hep4.1263

    PubMed

  11. Glycyrrhizin Alleviates Nonalcoholic Steatohepatitis via Modulating Bile Acids and Meta-Inflammation. Reviewed International journal

    Tingting Yan, Hong Wang, Lijuan Cao, Qiong Wang, Shogo Takahashi, Tomoki Yagai, Guolin Li, Kristopher W Krausz, Guangji Wang, Frank J Gonzalez, Haiping Hao

    Drug metabolism and disposition: the biological fate of chemicals   Vol. 46 ( 9 ) page: 1310 - 1319   2018.9

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    Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Glycyrrhizin (GL), extracted from the traditional Chinese medicine liquorice, has potent hepatoprotective effects in both preclinical animal models and in humans. However, little is currently known about its effects and mechanisms in treating NASH. To explore the effects of GL on NASH, GL or its active metabolite glycyrrhetinic acid (GA) was administered to mice treated with a methionine- and choline-deficient (MCD) diet-induced NASH model, and histologic and biochemical analyses were used to measure the degree of lipid disruption, liver inflammation, and fibrosis. GL significantly improved MCD diet-induced hepatic steatosis, inflammation, and fibrosis and inhibited activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. GL significantly attenuated serum bile acid accumulation in MCD diet-fed mice partially by restoring inflammation-mediated hepatic farnesoid X receptor inhibition. In Raw 264.7 macrophage cells, both GL and GA inhibited deoxycholic acid-induced NLRP3 inflammasome-associated inflammation. Notably, both intraperitoneal injection of GL's active metabolite GA and oral administration of GL prevented NASH in mice, indicating that GL may attenuate NASH via its active metabolite GA. These results reveal that GL, via restoration of bile acid homeostasis and inhibition of inflammatory injury, can be a therapeutic option for treatment of NASH.

    DOI: 10.1124/dmd.118.082008

    PubMed

  12. Structure-Activity Relationships of the Main Bioactive Constituents of Euodia rutaecarpa on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis. Reviewed International journal

    Youbo Zhang, Tingting Yan, Dongxue Sun, Cen Xie, Yiran Zheng, Lei Zhang, Tomoki Yagai, Kristopher W Krausz, William H Bisson, Xiuwei Yang, Frank J Gonzalez

    Drug metabolism and disposition: the biological fate of chemicals   Vol. 46 ( 7 ) page: 1030 - 1040   2018.7

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    Rutaecarpine (RUT), evodiamine (EOD), and dehydroevodiamine (DHED) are the three main bioactive indoloquinazoline alkaloids isolated from Euodia rutaecarpa, a widely prescribed traditional Chinese medicine. Here, the structure-activity relationships of these analogs for aryl hydrocarbon receptor (AHR) activation were explored by use of Ahr-deficient (Ahr-/-) mice, primary hepatocyte cultures, luciferase reporter gene assays, in silico ligand-docking studies, and metabolomics. In vitro, both mRNA analysis of AHR target genes in mouse primary hepatocytes and luciferase reporter assays in hepatocarcinoma cell lines demonstrated that RUT, EOD, and DHED significantly activated AHR, with an efficacy order of RUT > DHED > EOD. Ligand-docking analysis predicted that the methyl substitute at the N-14 atom was a key factor affecting AHR activation. In vivo, EOD was poorly orally absorbed and failed to activate AHR, whereas RUT and DHED markedly upregulated expression of the hepatic AHR gene battery in wild-type mice, but not in Ahr-/- mice. Furthermore, RUT, EOD, and DHED were not hepatotoxic at the doses used; however, RUT and DHED disrupted bile acid homeostasis in an AHR-dependent manner. These findings revealed that the methyl group at the N-14 atom of these analogs and their pharmacokinetic behaviors were the main determinants for AHR activation, and suggest that attention should be given to monitoring bile acid metabolism in the clinical use of E. rutaecarpa.

    DOI: 10.1124/dmd.117.080176

    PubMed

  13. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. Reviewed International journal

    Cen Xie, Tomoki Yagai, Yuhong Luo, Xianyi Liang, Tao Chen, Qiong Wang, Dongxue Sun, Jie Zhao, Sadeesh K Ramakrishnan, Lulu Sun, Chunmei Jiang, Xiang Xue, Yuan Tian, Kristopher W Krausz, Andrew D Patterson, Yatrik M Shah, Yue Wu, Changtao Jiang, Frank J Gonzalez

    Nature medicine   Vol. 23 ( 11 ) page: 1298 - 1308   2017.11

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    Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.

    DOI: 10.1038/nm.4412

    PubMed

  14. Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree. Reviewed International journal

    Tomoki Yagai, Satoshi Matsui, Kenichi Harada, Fuyuki F Inagaki, Eiko Saijou, Yasushi Miura, Yasuni Nakanuma, Atsushi Miyajima, Minoru Tanaka

    PloS one   Vol. 12 ( 4 ) page: e0175355   2017

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    Cholangiocarcinoma (CC) is a type of relatively rare neoplasm in adenocarcinoma. The characteristics of CCs as well as biliary epithelial cells are heterogeneous at the different portion of the biliary tree. There are two candidate stem/progenitor cells of the biliary tree, i.e., biliary tree stem/progenitor cell (BTSC) at the peribiliary gland (PBG) of large bile ducts and liver stem/progenitor cell (LPC) at the canals of Hering of peripheral small bile duct. Although previous reports suggest that intrahepatic CC (ICC) can arise from such stem/progenitor cells, the characteristic difference between BTSC and LPC in pathological process needs further investigation, and the etiology of CC remains poorly understood. Here we show that Sterile alpha motif domain containing 5 (SAMD5) is exclusively expressed in PBGs of large bile ducts in normal mice. Using a mouse model of cholestatic liver disease, we demonstrated that SAMD5 expression was upregulated in the large bile duct at the hepatic hilum, the extrahepatic bile duct and PBGs, but not in proliferating intrahepatic ductules, suggesting that SAMD5 is expressed in BTSC but not LPC. Intriguingly, human ICCs and extrahepatic CCs exhibited striking nuclear localization of SAMD5 while the normal hilar large bile duct displayed slight-to-moderate expression in cytoplasm. In vitro experiments using siRNA for SAMD5 revealed that SAMD5 expression was associated with the cell cycle regulation of CC cell lines. CONCLUSION: SAMD5 is a novel marker for PBG but not LPC in mice. In humans, the expression and location of SAMD5 could become a promising diagnostic marker for the cell type as well as malignancy of bile ducts and CCs.

    DOI: 10.1371/journal.pone.0175355

    PubMed

  15. The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4. Reviewed International journal

    Xiaoxia Gao, Cen Xie, Yuanyuan Wang, Yuhong Luo, Tomoki Yagai, Dongxue Sun, Xuemei Qin, Kristopher W Krausz, Frank J Gonzalez

    Biochemical pharmacology   Vol. 119   page: 93 - 104   2016.11

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    Flutamide (FLU), an oral, nonsteroidal antiandrogen drug used in the treatment of prostate cancer, is associated with idiosyncratic hepatotoxicity that sometimes causes severe liver damage, including cholestasis, jaundice, and liver necrosis. To understand the mechanism of toxicity, a combination of aryl hydrocarbon receptor (Ahr)-deficient (Ahr-/-) mice, primary hepatocytes, luciferase reporter gene assays, in silico ligand docking and ultra-performance chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics was used. A significant increase of liver weights, and liver and serum bile acid levels was observed after FLU treatment, indicating hepatomegaly and disrupted bile acid homeostasis. Expression of the AhR gene battery was markedly increased in livers of wild-type mice Ahr+/+ treated with FLU, while no change was noted in Ahr-/- mice. Messenger RNAs encoded by AhR target genes were induced in primary mouse hepatocytes cultured with FLU, which confirmed the in vivo results. Ligand-docking analysis further predicted that FLU is an AhR agonist ligand which was confirmed by luciferase reporter gene assays. Multivariate data analysis showed that bile acids were responsible for the separation of vehicle- and FLU-treated Ahr+/+ mice, while there was no separation in Ahr-/- mice. Expression of mRNA encoding the bile acid transporter ABCC4 was increased and farnesoid X receptor signaling was inhibited in the livers of Ahr+/+ mice, but not in Ahr-/- mice treated with FLU, in agreement with the observed downstream metabolic alterations. These findings provide new insights into the mechanism of liver injury caused by FLU treatment involving activation of AhR and the alterations of bile acid homeostasis, which could guide clinical application.

    DOI: 10.1016/j.bcp.2016.08.021

    PubMed

  16. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor α-Mediated Apoptosis. Reviewed International journal

    Tingting Yan, Hong Wang, Min Zhao, Tomoki Yagai, Yingying Chai, Kristopher W Krausz, Cen Xie, Xuefang Cheng, Jun Zhang, Yuan Che, Feiyan Li, Yuzheng Wu, Chad N Brocker, Frank J Gonzalez, Guangji Wang, Haiping Hao

    Drug metabolism and disposition: the biological fate of chemicals   Vol. 44 ( 5 ) page: 720 - 31   2016.5

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    Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factorα(TNFα)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP-induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFα-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFα-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose.

    DOI: 10.1124/dmd.116.069419

    PubMed

  17. Semaphorin 3E secreted by damaged hepatocytes regulates the sinusoidal regeneration and liver fibrosis during liver regeneration. Reviewed International journal

    Tomoki Yagai, Atsushi Miyajima, Minoru Tanaka

    The American journal of pathology   Vol. 184 ( 8 ) page: 2250 - 9   2014.8

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    The liver has a remarkable capacity to regenerate after injury. Although the regulatory mechanisms of hepatocytic regeneration have been a subject of intense study, the dynamism of the sinusoids, specialized blood vessels in the liver, remains largely unknown. Transient activation of hepatic stellate cells and hepatic sinusoidal endothelial cells, which constitute the sinusoids, contributes to liver regeneration during acute injury, whereas their sustained activation causes liver fibrosis during chronic injury. We focused on understanding the association between damaged hepatocytes and sinusoidal regeneration or liver fibrogenesis using a carbon tetrachloride-induced liver injury mouse model. Damaged hepatocytes rapidly expressed semaphorin 3E (Sema3e), which induced contraction of sinusoidal endothelial cells and thereby contributed to activating hepatic stellate cells for wound healing. In addition, ectopic and consecutive expression of Sema3e in hepatocytes by the hydrodynamic tail-vein injection method resulted in disorganized regeneration of sinusoids and sustained activation of hepatic stellate cells. In contrast, liver fibrosis ameliorated in Sema3e-knockout mice compared with wild-type mice in a chronic liver injury model. Our results indicate that Sema3e, secreted by damaged hepatocytes, affects sinusoidal regeneration in a paracrine manner during liver regeneration, suggesting that Sema3e is a novel therapeutic target in liver fibrogenesis.

    DOI: 10.1016/j.ajpath.2014.04.018

    PubMed

  18. Characterization of vitellogenin and its derived yolk proteins in cloudy catshark (Scyliorhinus torazame). Reviewed International journal

    Kodai Yamane, Tomoki Yagai, Osamu Nishimiya, Rieko Sugawara, Haruna Amano, Toshiaki Fujita, Naoshi Hiramatsu, Takashi Todo, Takahiro Matsubara, Akihiko Hara

    Fish physiology and biochemistry   Vol. 39 ( 2 ) page: 373 - 90   2013.4

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    Elasmobranchs (sharks and rays) exhibit unique reproductive characteristics and, in contrast to the situation in teleosts, very little is known about the identity, structure and physical characteristics of their egg yolk proteins. The aims of this study were to (1) detect and purify the vitellogenin (Vtg; egg yolk precursor) and yolk proteins (YPs) of the cloudy catshark (Scyliorhinus torazame), (2) examine the relationships between Vtg and YPs and (3) characterize and classify the deduced primary structure of the Vtg transcript (vtg). The apparent molecular weights of purified Vtg and putative Vtg-related YPs (lipovitellin: Lv, phosvitin: Pv) were determined by gel filtration and were ~560, >669 and ~58 kDa, respectively. Following SDS-PAGE, these purified products (i.e., Vtg, Lv and Pv) appeared as bands of ~210, ~110 and ~22 kDa, respectively. On Western blots, antisera against purified Vtg, Lv and Pv recognized the ~210 kDa Vtg band. Catshark Pv, in contrast to teleost Pvs, had a very low serine content. The catshark Vtg cDNA sequence (vtg) appeared to contain an open-reading frame consisting of domains encoding Lv, Pv and β'-component (β'-c). A phylogenetic analysis, with a consideration of genome duplication events, placed catshark vtg into the 'vtgAB type.' It is concluded that at least a single major type of Vtg protein, which is transcribed and translated from catshark vtgAB gene, is the precursor of three egg yolk proteins (Lv, Pv and β'-c) in catshark.

    DOI: 10.1007/s10695-012-9706-1

    PubMed

  19. Nephronectin is upregulated in acute and chronic hepatitis and aggravates liver injury by recruiting CD4 positive cells. Reviewed International journal

    Fuyuki F Inagaki, Minoru Tanaka, Natsuko F Inagaki, Tomoki Yagai, Yuya Sato, Kiyotoshi Sekiguchi, Naoki Oyaizu, Norihiro Kokudo, Atsushi Miyajima

    Biochemical and biophysical research communications   Vol. 430 ( 2 ) page: 751 - 6   2013.1

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    Nephronectin (Npnt) is an extracellular matrix protein known to play a critical role in kidney development; however, its physiological role in the liver remains elusive. Here we show that Npnt expression is upregulated in mouse models of both acute and chronic hepatitis induced by Concanavalin A (Con A) and 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC), respectively. In both models, Npnt was localized in inflammatory foci and was mainly secreted from mesenchymal cells and in part by cholangiocytes. Interestingly, ectopic expression of Npnt in hepatocytes induced the development of granuloma-like cell clusters mainly composed of CD4(+) T cells or NKT cells but did not induce apparent hepatitis. Furthermore, we found that Npnt exacerbated the Con A-induced acute hepatitis. These results indicate that Npnt plays an important role in the initiation of hepatitis by recruiting CD4(+) T cells or NKT cells into the foci of inflammation. In addition, we reveal that Npnt expression is also upregulated in human hepatitis. Therefore, Npnt may be a potential therapeutic target for acute and chronic hepatitis.

    DOI: 10.1016/j.bbrc.2012.11.076

    PubMed

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MISC 6

  1. 非アルコール性脂肪性肝炎における脂肪酸とエクソソームの作用機序の解析

    谷貝知樹

    三島海雲記念財団研究報告書(CD-ROM)   ( 58 ) page: 1 - 4   2021

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    Language:Japanese   Publisher:三島海雲記念財団  

    J-GLOBAL

  2. 肝脂質代謝に関わるPPARα-制御性microRNAの新規機能の解析

    谷貝知樹, BROCKER Chad, BROCKER Chad, KIM Donghwan, 高橋昌悟, 高橋昌悟, GAVRILOVA Oksana, GONZALEZ Frank

    肝細胞研究会プログラム・抄録集   Vol. 26th   2019

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  3. 胆管傷害および胆管癌におけるsterile alpha motif domain containing5の発現解析

    谷貝知樹, 松井理司, 原田憲一, 中沼安二, 稲垣冬樹, 西條栄子, 宮島篤, 田中稔

    肝細胞研究会プログラム・抄録集   Vol. 21st   page: 3P - 434   2014

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    Language:Japanese   Publisher:(公社)日本生化学会  

    J-GLOBAL

  4. 肝細胞死から見た肝障害後の再生および線維化の制御機構

    田中稔, 谷貝知樹, 宮島篤

    日本生化学会大会(Web)   Vol. 86th   page: 1S17p - 4   2013.9

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    Language:Japanese   Publisher:(公社)日本生化学会  

    J-GLOBAL

  5. 胆管傷害および胆管癌におけるsterile alpha motif domain containing5の発現解析

    谷貝知樹, 田中稔, 原田憲一, 中沼安二, 稲垣冬樹, 西條栄子, 宮島篤

    日本生化学会大会(Web)   Vol. 86th   2013

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  6. 肝再生および肝線維化におけるSemaphorin 3Eの機能(Function of Semaphorin 3E in liver fibrosis and regeneration)

    谷貝 知樹, 田中 稔, 宮島 篤

    日本生化学会大会プログラム・講演要旨集   Vol. 85回   page: 3T24 - 09   2012.12

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Presentations 3

  1. PPARα-SMPD3 axis regulates hepatic lipid accumulation and inflammation in NAFLD/NASH

    Tomoki Yagai

    Joint Meeting of ASMB, HCS, and ASIP  2023.10.24 

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    Event date: 2023.10

    Language:English   Presentation type:Poster presentation  

  2. A novel role for a PPARα-regulated microRNA in the control of hepatic lipid metabolism

    Yagai T, Brocker CN, Kim D, Takahashi S, Gonzalez FJ

    Keystone Symposium - Integrated Pathways of Disease in NASH and NAFLD 

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    Event date: 2019.1

  3. Semaphorin 3E secreted by damaged hepatocytes regulates the sinusoidal regeneration and liver fibrosis during mouse liver regeneration

    Yagai T, Miyajima A, Tanaka M

    Keystone Symposium, Fibrosis: From Bench to Bedside 

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    Event date: 2013.3

Other research activities 1

  1. 日本学生支援機構大学院第一種奨学金 全額返還免除認定

    2014

KAKENHI (Grants-in-Aid for Scientific Research) 6

  1. 脂肪肝由来エクソソームのNASH増悪化における役割の解明

    2022.3 - 2023.3

    公益財団法人 小野医学研究財団  研究奨励助成金 

    谷貝 知樹

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    Authorship:Principal investigator 

  2. NRF2活性化型肺癌細胞と癌微小環境における細胞外小胞を介した癌増悪化メカニズムの解明

    2021.9 - 2023.3

    公益財団法人 武田科学振興財団  医学系研究助成 

    谷貝 知樹

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    Authorship:Principal investigator 

  3. 脂肪肝・NASHにおけるエクソソームを介した炎症制御機構の解明

    2021.9 - 2022.8

    公益財団法人 艮陵医学振興会  医学研究助成金 

    谷貝 知樹

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    Authorship:Principal investigator 

  4. 非アルコール性脂肪性肝炎における脂肪酸とエクソソームの作用機序の解析

    2020.7 - 2021.6

    公益財団法人 三島海雲記念財団  学術研究奨励金 

    谷貝 知樹

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    Authorship:Principal investigator 

  5. PPARαによる炎症性エクソソーム制御を介した抗炎症作用の分子基盤解析

    Grant number:20K16152  2020.4 - 2024.3

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    谷貝 知樹

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

  6. 細胞外小胞を介した炎症反応誘導機構の分子基盤解析

    Grant number:20H03445  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    中村 能久, 谷貝 知樹, 本橋 ほづみ, 北村 大志

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    Authorship:Coinvestigator(s) 

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