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Association of oxysterol imbalance in disease progression of non alcoholic steathepatitis

Research Project

Project/Area Number 16K09377
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical University

Principal Investigator

Ikegami Tadashi  東京医科大学, 医学部, 教授 (40439740)

Co-Investigator(Kenkyū-buntansha) 本多 彰  東京医科大学, 医学部, 教授 (10468639)
宮崎 照雄  東京医科大学, 医学部, 講師 (60532687)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Keywords酸化ステロール / 胆汁酸 / acidic pathway / NASH / 非アルコール性脂肪性肝炎 / コレステロール代謝 / Farnesoid X receptor / 肝細胞癌 / マクロファージ / CYP27A1
Outline of Final Research Achievements

The deficiency of lipid/carbohydrate metabolism via the suppression of nuclear receptor FXR-mediated signaling has been thought as a cause of NASH, and agonists for FXR are used as therapeutic agents in overseas. In this study, we confirmed that FXR stimulation reduced fat deposition in hepatocytes of immortalized human hepatocytes. On the other hand, the serum bile acid composition of Japanese NASH patients showed increased ligand binding affinity to FXR as agonist in theoretical calculation. However, C4, a surrogate marker of CYP7A1 suppressed by FXR activation, remained unchanged in patients with NASH. These findings raise a new question as to whether FXR signaling is suppressed in Japanese NASH.

Academic Significance and Societal Importance of the Research Achievements

酸化ステロールの発生場所と考えたマクロファージについて注目したが、直接的に細胞内での発現レベルなどを解析するまでには至らなかった。しかし、酵素的酸化ステロールが生まれる胆汁酸合成経路のAcidic pathwayがNASH患者では優位になっていること、さらにacidic pathwayで産生されるCDCAが炎症性サイトカインの産生を介してFXRシグナリングとは別の経路で病態に関与していることが示された。これらのデータから、人種差や動物の種差などの影響が無視できないことがわかり、特に胆汁酸代謝を変動させる薬剤について、今後前臨床データの解釈には注意を払う必要があることを示した。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (32 results)

All 2020 2019 2018 2017 2016

All Journal Article (17 results) (of which Peer Reviewed: 17 results,  Open Access: 7 results) Presentation (14 results) (of which Int'l Joint Research: 3 results) Book (1 results)

  • [Journal Article] Regulations of bile acid metabolism in mouse models with hydrophobic bile acid composition.2020

    • Author(s)
      Honda A, Miyazaki T, Iwamoto J, Hirayama T, Morishita Y, Monma T, Ueda H, Mizuno S, Sugiyama F, Takahashi S, Ikegami T.
    • Journal Title

      Journal of Lipid Research

      Volume: 61 Issue: 1 Pages: 54-69

    • DOI

      10.1194/jlr.ra119000395

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Circulating bile acid profiles in Japanese patients with NASH2020

    • Author(s)
      Yara, S. Ikegami, T. Miyazaki, T. Murakami, M. Iwamoto, J. Hirayama, T. Kohjima, M. Nakamuta, M. Honda, A.
    • Journal Title

      GasroHep

      Volume: 1 Issue: 6 Pages: 302-310

    • DOI

      10.1002/ygh2.374

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impaired bile acid metabolism with defectives of mitochondrial-tRNA taurine modification and bile acid taurine conjugation in the taurine depleted cats2020

    • Author(s)
      Miyazaki Teruo、Sasaki Sei-Ich、Toyoda Atsushi、Wei Fan-Yan、Shirai Mutsumi、Morishita Yukio、Ikegami Tadashi、Tomizawa Kazuhito、Honda Akira
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 4915-4915

    • DOI

      10.1038/s41598-020-61821-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study2020

    • Author(s)
      Nozaki, A. Atsukawa, M. Ogawa, S. Itokawa, N. Arai, T. Ikegami, T. Tsubota, A. Genda, T. Okubo, H. Mikami, S. Morishita, A. Moriya, A. Tani, J. Tachi, Y. Hotta, N. Ishikawa, T. Okanoue, T. Tanaka, Y. Kumada, T. Iwakiri, K. Maeda, S. K. T. K. Liver Study Group
    • Journal Title

      Hepatol Int

      Volume: - Issue: 2 Pages: 225-238

    • DOI

      10.1007/s12072-020-10019-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real-world setting: A large, multicenter study from Japan2020

    • Author(s)
      Toyoda H, Atsukawa M, Watanabe T..., Tsubota A, et al
    • Journal Title

      J Gastroenterol Hepatol

      Volume: - Issue: 8 Pages: 1420-1425

    • DOI

      10.1111/jgh.14982

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influences of Taurine Deficiency on Bile Acids of the Bile in the Cat Model2019

    • Author(s)
      Miyazaki, T. Sasaki, S. I. Toyoda, A. Shirai, M. Ikegami, T. Matsuzaki, Y. Honda, A.
    • Journal Title

      Adv Exp Med Biol

      Volume: 1155 Pages: 35-44

    • DOI

      10.1007/978-981-13-8023-5_4

    • ISBN
      9789811380228, 9789811380235
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan2019

    • Author(s)
      Toyoda H, Atsukawa M, Uojima H, Nozaki A, Tamai H, Takaguchi K, Fujioka S, Nakamuta M, Tada T, Yasuda S, Chuma M, Senoh T, Tsutsui A, Yamashita N, Hiraoka A, Michitaka K, Shima T, Akahane T, Itobayashi E, Watanabe T, et al.
    • Journal Title

      Open Forum Infectious Diseases

      Volume: 6 Issue: 5

    • DOI

      10.1093/ofid/ofz185

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Real‐world experience of 12‐week direct‐acting antiviral regimen of glecaprevir and pibrentasvir in patients with chronic hepatitis C virus infection2019

    • Author(s)
      Toyoda H, Atsukawa M, Watanabe T, et al
    • Journal Title

      Journal of Gastroenterology and Hepatology

      Volume: - Issue: 5 Pages: 855-861

    • DOI

      10.1111/jgh.14874

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human-specific dual regulations of FXR-activation for reduction of fatty liver using <i>in vitro</i> cell culture model2019

    • Author(s)
      Miyazaki T, Honda A, Ikegami T, Iida T, Matsuzaki Y
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 64 Issue: 2 Pages: 112-123

    • DOI

      10.3164/jcbn.18-80

    • NAID

      130007606956

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The efficacy and safety of glecaprevir plus pibrentasvir in 141 patients with severe renal impairment: a prospective, multicenter study.2019

    • Author(s)
      Atsukawa M, Tsubota A, Toyoda H, Takaguchi K, Nakamuta M, Watanabe T, Michitaka K, Ikegami T, Nozaki A, Uojima H, Fukunishi S, Genda T, Abe H, Hotta N, Tsuji K, Ogawa C, Tachi Y, Shima T, Shimada N, Kondo C, Akahane T, Aizawa Y, Tanaka Y, Kumada T, Iwakiri K
    • Journal Title

      Aliment Pharmacol Ther

      Volume: 49 Issue: 9 Pages: 1230-1241

    • DOI

      10.1111/apt.15218

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy and safety of ombitasvir/paritaprevir/ritonavir and ribavirin for chronic hepatitis patients infected with genotype 2a in Japan.2019

    • Author(s)
      Atsukawa M, Tsubota A, Toyoda H, Takaguchi K, Nakamuta M, Watanabe T, Tada T, Tsutsui A, Ikeda H, Abe H, Kato K, Uojima H, Ikegami T, Asano T, Kondo C, Koeda M, Okubo T, Arai T, Iwashita-Nakagawa A, Itokawa N, Kumada T, Iwakiri K
    • Journal Title

      Hepatol Res

      Volume: 49 Issue: 4 Pages: 369-376

    • DOI

      10.1111/hepr.13292

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy of direct-acting antiviral treatment in patients with compensated liver cirrhosis: A multicenter study.2019

    • Author(s)
      Itokawa N, Atsukawa M, Tsubota A, Ikegami T, Shimada N, Kato K, Abe H, Okubo T, Arai T, Iwashita AN, Kondo C, Mikami S, Asano T, Matsuzaki Y, Toyoda H, Kumada T, Iio E, Tanaka Y, Iwakiri K
    • Journal Title

      Hepatol Res

      Volume: 49 Issue: 2 Pages: 125-135

    • DOI

      10.1111/hepr.13256

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Differences in the Serum 4β-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment2018

    • Author(s)
      Hirayama T, Ikegami T, Honda A, Miyazaki T, Yara SI, Kohjima M, Nakamuta M, Matsuzaki Y.
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 9 Pages: 1219-1227

    • DOI

      10.2169/internalmedicine.9479-17

    • NAID

      130006730718

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2018-05-01
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of Gut Dysbiosis due to Reduced Clostridium Subcluster XIVa Using the Fecal or Serum Bile Acid Profile.2018

    • Author(s)
      Murakami M, Iwamoto J, Honda A, Tsuji T, Tamamushi M, Ueda H, Monma T, Konishi N, Yara S, Hirayama T, Miyazaki T, Saito Y, Ikegami T, Matsuzaki Y.
    • Journal Title

      Inflamm Bowel Dis

      Volume: 24 Issue: 5 Pages: 1035-1044

    • DOI

      10.1093/ibd/izy022

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Reciprocal interactions between bile acids and gut microbiota in human liver diseases2018

    • Author(s)
      Ikegami T, Honda A
    • Journal Title

      Hepatol Res

      Volume: 48 Issue: 1 Pages: 15-27

    • DOI

      10.1111/hepr.13001

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of the Concomitant Use of Low-dose Clarithromycin with an Anti-TNFα Antibody in a Patient with Intestinal Behçet Disease2018

    • Author(s)
      Iwamoto J, Murakami M, Konishi N, Monma T, Ueda H, Yara S, Hirayama T, Ikegami T, Honda A, Matsuzaki Y.
    • Journal Title

      Internal Medicine

      Volume: 57 Issue: 3 Pages: 339-342

    • DOI

      10.2169/internalmedicine.9322-17

    • NAID

      130006329614

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of ombitasvir/paritaprevir/ritonavir in dialysis patients with genotype 1b chronic hepatitis C2017

    • Author(s)
      Atsukawa M, Tsubota A, Koushima Y, Ikegami T, Watanabe K, Shimada N, Sato S, Kato K, Abe H, Okubo T, Arai T, Itokawa N, Kondo C, Mikami S, Asano T, Chuganji Y, Matsuzaki Y, Iwakiri K.
    • Journal Title

      Hepatology Research

      Volume: 印刷中 Issue: 13 Pages: 1429-1437

    • DOI

      10.1111/hepr.12910

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] 食と腸肝相関:食事・腸内細菌・胆汁酸シグナリング2019

    • Author(s)
      池上 正、屋良昭一郎、本多 彰
    • Organizer
      JDDW2019 統合プログラム4 シンポジウム 食と消化器疾患
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規DAA治療患者の受療行動変容についての多施設調査報告2019

    • Author(s)
      池上 正、田中直見、荒木真裕、佐藤巳喜夫、長野具雄、仁平武、鴨志田敏郎、松崎靖司
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Roles of bile acids in hepatobiliary diseases: a novel approach using mouse model with humanized bile acid composition2019

    • Author(s)
      Honda,A. Miyazaki, T. Ikegami,T.
    • Organizer
      第23回肝臓学会大会 International Session (symposium 1) Pathogenesis and novel treatment of cholestatic liver dieseases
    • Related Report
      2019 Annual Research Report
  • [Presentation] 非アルコール性脂肪性肝炎の発生・進展における血中胆汁酸組成の変化2018

    • Author(s)
      池上 正・本多 彰・松崎靖司
    • Organizer
      第42回日本肝臓学会東部会 シンポジウム10 肝疾患と臓器相関
    • Related Report
      2018 Research-status Report
  • [Presentation] Hepatitis screening test during regular health checkup in workplace - A survey in a suburban region in Japan -2018

    • Author(s)
      Tadashi Ikegami, Teruo Miyazaki, Toshiro Kamoshida and Yasushi Matsuzaki
    • Organizer
      Liver meeting 2018, San Francisco, USA
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 乏血性病変を有するHCV症例に対するDAA治療2018

    • Author(s)
      玉虫惇、池上正、屋良昭一郎、村上昌、小西直樹、門馬匡邦、上田元、平山剛、岩本淳一、本多彰、松崎靖司
    • Organizer
      第54回日本肝癌研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] 茨城県多施設におけるDAA治療の実態調査2018

    • Author(s)
      屋良 昭一郎、池上正、荒木 眞裕、田中 直見、西 雅明、 廣島 良規、河村 貴広、池澤 和人、長野 具雄、佐藤巳喜夫、福田 邦明、浅岡 等、小島 眞樹、吉田 正、西村 泰彦、冨田 慎二、平山 剛、本多 彰、鴨志田 敏郎、松﨑 靖司
    • Organizer
      第54回日本肝臓学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 当院におけるレンバチニブの初期使用経験2018

    • Author(s)
      門馬匡邦、池上 正、平山 剛、屋良昭一郎、小西直樹、玉虫 惇、上田 元、村上 昌 岩本淳一、本多 彰、松崎靖司
    • Organizer
      第19回日本肝がん分子標的治療研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Gut-dysbiosis due to reduced Clostridium subcluster XIVa is associated with the progression of nonalcoholic fatty liver disease: analysis based on the serum bile acid profile2017

    • Author(s)
      Tadashi Ikegami, Akira Honda, Masashi Murakami, Shoichiro Yara, Teruo Miyazaki, Yasuyuki Kohjima, Makoto Nakamuta, Junichi Iwamoto, Yasushi Matsuzaki,
    • Organizer
      The liver meeting 2017 (Washington, DC. USA)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sorafenib使用歴のあるHCV 肝疾患患者に対するDAA治療2017

    • Author(s)
      池上 正、屋良昭一郎、小西直樹、門馬匡邦、村上 昌、平山 剛、上田 元、岩本淳一、本多 彰、松崎靖司
    • Organizer
      第16回日本肝がん分子標的治療研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 当院における肝細胞癌治療後のDAA治療2017

    • Author(s)
      池上 正、本多 彰、平山 剛、村上 昌、屋良昭一郎、小西直樹、門馬匡邦、岩本淳一、鈴木修司、松崎靖司
    • Organizer
      JDDW2017
    • Related Report
      2017 Research-status Report
  • [Presentation] オムビタスビル・パリタプレビル・リトナビル(OTV/PTV/r)投与によるCYP3A4活性サロゲートマーカーの変化2017

    • Author(s)
      池上 正、本多 彰、平山 剛、宮崎照雄、屋良昭一郎、小西直樹、門馬匡邦、村上 昌、岩本淳一、松崎靖司
    • Organizer
      JDDW2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Difference of serum 4beta-hdyroxycholesterol level, a surrogate marker of CYP3A activity , among patients with HCV infection2016

    • Author(s)
      Ikegami T, Honda A, Yara S, Konishi N, Murakami M, Monma T, Hirayama T, Miyazaki T, Iwamoto J, Matsuzaki Y
    • Organizer
      Liver meeting 2016
    • Place of Presentation
      Boston, MA, USA
    • Year and Date
      2016-11-11
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脂肪性肝炎進展過程における酸化ステロールの質的変化2016

    • Author(s)
      屋良昭一郎、池上 正、本多 彰、宮崎照雄、松崎靖司
    • Organizer
      JDDW 2016
    • Place of Presentation
      神戸市、兵庫県
    • Year and Date
      2016-11-03
    • Related Report
      2016 Research-status Report
  • [Book] Bile Acids in Gastroenterology2017

    • Author(s)
      Honda A, Ikegami T, Matsuzaki Y. Edited by Tazume S and Takikawa H
    • Total Pages
      209
    • Publisher
      Springer
    • ISBN
      9784431560623
    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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