Association of oxysterol imbalance in disease progression of non alcoholic steathepatitis

• Project/Area Number: 16K09377
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo 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: ¥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。

Research Products

• [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
  • Peer Reviewed
• [Journal Article] Circulating bile acid profiles in Japanese patients with NASH (2020)
  • 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
  • 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 cats (2020)
  • 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
  • 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 study (2020)
  • 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
  • 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 Japan (2020)
  • 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
  • Peer Reviewed
• [Journal Article] Influences of Taurine Deficiency on Bile Acids of the Bile in the Cat Model (2019)
  • 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
  • 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 Japan (2019)
  • 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
  • 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 infection (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Human-specific dual regulations of FXR-activation for reduction of fatty liver using <i>in vitro</i> cell culture model (2019)
  • 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
  • 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
  • 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
  • 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
  • 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 Treatment (2018)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Reciprocal interactions between bile acids and gut microbiota in human liver diseases (2018)
  • Author(s): Ikegami T, Honda A
  • Journal Title: Hepatol Res Volume: 48 Issue: 1 Pages: 15-27
  • DOI: 10.1111/hepr.13001
  • Peer Reviewed
• [Journal Article] Effects of the Concomitant Use of Low-dose Clarithromycin with an Anti-TNFα Antibody in a Patient with Intestinal Behçet Disease (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of ombitasvir/paritaprevir/ritonavir in dialysis patients with genotype 1b chronic hepatitis C (2017)
  • 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
  • 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
• [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
• [Presentation] Roles of bile acids in hepatobiliary diseases: a novel approach using mouse model with humanized bile acid composition (2019)
  • 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
• [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
• [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
  • 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
• [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
• [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
• [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 profile (2017)
  • 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)
  • 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
• [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
• [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
• [Presentation] Difference of serum 4beta-hdyroxycholesterol level, a surrogate marker of CYP3A activity , among patients with HCV infection (2016)
  • 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
  • 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
• [Book] Bile Acids in Gastroenterology (2017)
  • Author(s): Honda A, Ikegami T, Matsuzaki Y. Edited by Tazume S and Takikawa H
  • Total Pages: 209
  • Publisher: Springer
  • ISBN: 9784431560623