Immunonutritional approach for innate immune dysregulation in metabolic dysfunction-associated fatty liver disease

• Project/Area Number: 21K07922
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Juntendo University
• Principal Investigator: 池嶋 健一 順天堂大学, 医学部, 教授 (20317382)
• Co-Investigator(Kenkyū-buntansha): 今 一義 順天堂大学, 医学部, 准教授 (30398672) ; 山科 俊平 順天堂大学, 医学部, 先任准教授 (30338412)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 代謝障害性脂肪性肝疾患（MAFLD） / メタボリックシンドローム / 非アルコール性脂肪肝炎（NASH） / 非アルコール性脂肪性肝疾患（NAFLD） / サイトカイン・ストーム / リポポリサッカライド（LPS） / エンドトキシン・ショック / 細胞死 / 代謝性障害性脂肪肝疾患（MAFLD） / 非アルコール性脂肪肝炎（NASH) / COVID-19 / 腸内細菌叢 / 腸肝相関 / 自然免疫 / サイトカインストーム / 日本食

Outline of Research at the Start

メタボリックシンドロームに伴う代謝障害性脂肪性肝疾患（MAFLD）は新型コロナウイルスCOVID-19感染症の予後不良因子でもある。本研究では、MAFLDにおける腸内マイクロバイオームの変化と腸管透過性亢進に伴う肝内自然免疫応答の変化が、サイトカインストーム誘発に寄与していることを明らかにする。さらに、日本食を中心とした栄養介入によるMAFLDの肝病態改善効果および免疫制御機転を検証する。

Outline of Annual Research Achievements

本研究では、メタボリックシンドロームと関連の深い代謝障害性脂肪性肝疾患（MAFLD）の肝病態進展メカニズム解析に加えて、COVID-19など多くの急性疾患の予後に深く関与するサイトカイン・ストームの発生に与える影響を解明することを目的としている。前年度より、メタボリックシンドロームのモデル動物であるKK-Ayマウスでは高脂肪食（HFD）負荷によりエンドトキシン（LPS）肝障害が増悪し、致死率も有意に高まることを明らかにしてきた。そこで今年度はKK-AyマウスにおけるLPS投与後の肝内サイトカイン発現動態について検証した。肝内のTNFαおよびIL-1βmRNA発現はLPS投与1時間後をピークに上昇するが、HFD摂餌KK-Ayマウスではそのピーク値が有意に高値になることが判明した。LPS投与後に生じる肝組織中のF4/80陽性マクロファージの集積が高脂肪食摂餌群でより顕著であり、肝内CXCL2およびCXCL10などのケモカイン発現亢進も認められた。これらの事象より、サイトカイン・ストームの惹起がLPS肝障害増悪および致死率上昇に関与していることが確認された。さらに、LPS感受性亢進の成因として、HFD摂餌KK-AyマウスではLPS投与前から肝組織中のCD14発現亢進およびLPS-binding protein（LBP）mRNA発現誘導が認められることが明らかになった。実際、HFD摂餌によりKK-AyマウスではLPS未投与でもIL-6 mRNA発現が著明に亢進しており、IL-6作動性に肝細胞でのLBP誘導を生じていると考えられた。これらの変化はコントロールのC57Bl/6マウスにHFDを摂餌させても生じないことから、KK-Ayマウスではメタボリックシンドロームを形成する遺伝的素因に加えてHFDで惹起される脂肪肝炎がLPS感受性増大に寄与していることが示唆された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究ではメタボリックシンドローム関連脂肪性肝疾患におけるサイトカインストーム誘発の成因を明らかにすることを主たる目的としているが、今年度の研究では、前年度に検証したHFD摂餌KK-AyマウスにおけるLPS感受性増大のメカニズムとして、脂肪肝炎に伴うIL-6誘導およびLBP発現亢進が寄与していることが明らかになっており、比較的順調な進捗と考えている。

Strategy for Future Research Activity

KK-AyマウスにおけるHFD摂餌に伴うパターン認識受容体（PRR）発現動態およびLBP発現誘導のメカニズムについて解析を行う。また、HFD負荷により肝内発現亢進を認めたCD14およびLBP発現亢進について、単離細胞ないしセルラインを用いたin vitroでの解析を加える予定である。また、LPS投与後の肝細胞傷害については、アポトーシス以外の細胞死の関与についても引き続き検討を行う。さらに、免疫栄養アプローチによるLPS感受性低減の可能性について実験治療を試みる予定である。

Research Products

• [Journal Article] Endobronchial Watanabe Spigot Placement for Hepatic Abscess and Bronchobiliary Fistula Following Radiofrequency Ablation for Hepatocellular Carcinoma (2023)
  • Author(s): Nishioki Toshihiko、Koyama Ryo、Okubo Hironao、Fukuo Yuka、Takasaki Yusuke、Yae Toshifumi、Banno Takamitsu、Kido Kenji、Takahashi Kazuhisa、Shiina Shuichiro、Ikejima Kenichi
  • Journal Title: Internal Medicine Volume: 62 Issue: 7 Pages: 999-1004
  • DOI: 10.2169/internalmedicine.0392-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2023-04-01
  • Peer Reviewed
• [Journal Article] MR Fingerprinting for Liver Tissue Characterization: A Histopathologic Correlation Study. (2023)
  • Author(s): Fujita S, Sano K, Cruz G, Fukumura Y, Kawasaki H, Fukunaga I, Morita Y, Yoneyama M, Kamagata K, Abe O, Ikejima K, Botnar RM, Prieto C, Aoki S.
  • Journal Title: Radiology Volume: 306 Issue: 1 Pages: 150-159
  • DOI: 10.1148/radiol.220736
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Impact of Partial Splenic Embolization on Portal Hypertensive Gastropathy in Cirrhotic Patients with Portal Hypertension (2023)
  • Author(s): Saeki Michio、Okubo Hironao、Takasaki Yusuke、Nakadera Eisuke、Fukuo Yuka、Fukada Hiroo、Hotchi Yuta、Maruyama Hitoshi、Kokubu Shigehiro、Shiina Shuichiro、Nagahara Akihito、Ikejima Kenichi
  • Journal Title: Journal of Clinical Medicine Volume: 12 Issue: 7 Pages: 2662-2662
  • DOI: 10.3390/jcm12072662
  • Peer Reviewed / Open Access
• [Journal Article] Gadoxetic acid-enhanced magnetic resonance imaging predicts hyperbilirubinemia induced by glecaprevir during hepatitis C virus treatment (2022)
  • Author(s): Okubo Hironao、Atsukawa Masanori、Okubo Tomomi、Ando Hitoshi、Nakadera Eisuke、Ikejima Kenichi、Nagahara Akihito
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 7847-7847
  • DOI: 10.1038/s41598-022-11707-6
  • Peer Reviewed / Open Access
• [Journal Article] Autophagic dysfunction in the liver enhances the expression of insoluble nuclear proteins 14-3-3ζ and importin α4 (2022)
  • Author(s): Kousuke Izumi , Shunhei Yamashina , Tsutomu Fujimura, Sumio Watanabe , Kenichi Ikejima
  • Journal Title: Life Sci. Volume: 298 Pages: 120491-120491
  • DOI: 10.1016/j.lfs.2022.120491
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Cabozantinib Exposure on Proteinuria and Muscle Toxicity in Patients with Unresectable Hepatocellular Carcinoma (2022)
  • Author(s): Okubo Hironao、Ando Hitoshi、Takasaki Yusuke、Nakadera Eisuke、Fukuo Yuka、Shiina Shuichiro、Ikejima Kenichi
  • Journal Title: Pharmaceuticals Volume: 15 Issue: 12 Pages: 1460-1460
  • DOI: 10.3390/ph15121460
  • Peer Reviewed / Open Access
• [Journal Article] Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA (2022)
  • Author(s): Someya Shunin、Uchiyama Akira、Arai Kumiko、Kon Kazuyoshi、Yamashina Shunhei、Watanabe Sumio、Ikejima Kenichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 588 Pages: 90-96
  • DOI: 10.1016/j.bbrc.2021.12.011
  • Peer Reviewed
• [Journal Article] Carbohydrate-deficient transferrin is a sensitive marker of alcohol consumption in fatty liver disease (2022)
  • Author(s): Morinaga Maki、Kon Kazuyoshi、Uchiyama Akira、Fukada Hiroo、Fukuhara Kyoko、Yaginuma Reiko、Nakadera Eisuke、Yamashina Shunhei、Ikejima Kenichi
  • Journal Title: Hepatology International Volume: 16 Issue: 2 Pages: 348-358
  • DOI: 10.1007/s12072-022-10298-8
  • Peer Reviewed
• [Journal Article] Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury. (2021)
  • Author(s): Enzhi Yin, Takeshi Fukuhara, Kazuyoshi Takeda, Yuko Kojima, Kyoko Fukuhara, Kenichi Ikejima, Hisashi Bashuda, Jiro Kitaura, Hideo Yagita, Ko Okumura, Koichiro Uchida
  • Journal Title: Scientific Reports Volume: 6322 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-021-85001-2
  • Peer Reviewed / Open Access
• [Journal Article] Evidence‐based clinical?practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020 (2021)
  • Author(s): Tokushige Katsutoshi、Ikejima Kenichi、Ono Masafumi、Eguchi Yuichiro、Kamada Yoshihiro、Itoh Yoshito、Akuta Norio、Yoneda Masato、Iwasa Motoh、Yoneda Masashi、Otsuka Motoyuki、Tamaki Nobuharu、Kogiso Tomomi、Miwa Hiroto、Chayama Kazuaki、Enomoto Nobuyuki、Shimosegawa Tooru、Takehara Tetsuo、Koike Kazuhiko
  • Journal Title: Hepatology Research Volume: 51 Issue: 10 Pages: 1013-1025
  • DOI: 10.1111/hepr.13688
  • Peer Reviewed / Open Access
• [Journal Article] Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020 (2021)
  • Author(s): Tokushige Katsutoshi、Ikejima Kenichi、Ono Masafumi、Eguchi Yuichiro、Kamada Yoshihiro、Itoh Yoshito、Akuta Norio、Yoneda Masato、Iwasa Motoh、Yoneda Masashi、Otsuka Motoyuki、Tamaki Nobuharu、Kogiso Tomomi、Miwa Hiroto、Chayama Kazuaki、Enomoto Nobuyuki、Shimosegawa Tooru、Takehara Tetsuo、Koike Kazuhiko
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 11 Pages: 951-963
  • DOI: 10.1007/s00535-021-01796-x
  • Peer Reviewed / Open Access
• [Journal Article] Levocarnitine Supplementation Suppresses Lenvatinib-Related Sarcopenia in Hepatocellular Carcinoma Patients: Results of a Propensity Score Analysis (2021)
  • Author(s): Okubo Hironao、Ando Hitoshi、Nakadera Eisuke、Ikejima Kenichi、Shiina Shuichiro、Nagahara Akihito
  • Journal Title: Nutrients Volume: 13 Issue: 12 Pages: 4428-4428
  • DOI: 10.3390/nu13124428
  • Peer Reviewed / Open Access
• [Presentation] A selective PPARα modulator pemafibrate reduced palmitic acid-induced lipotoxicity via induction of autophagy. (2023)
  • Author(s): Shunhei Yamashina, Satoshi Sakuma, Toshifumi Sato, Hiroo Fukada, Hisafumi Yamagata, Akira Uchiyama, Reiko Yaginuma, Kyoko Fukuhara, Kazuyoshi Kon, Kenichi Ikejima.
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2023 Taipei
  • Int'l Joint Research
• [Presentation] Diagnosis of Perihepatitis and Fitz-Hugh-Curtis Syndrome by Laparoscopy: An Unusual Condition for Right Hypochondriac Pain and Liver Injury? (2023)
  • Author(s): Shunsuke Ikejima, Akira Uchiyama, Maki Morinaga, Hiroo Fukada, Hisafumi Yamagata, Reiko Yaginuma, Kyoko Fukuhara, Kazuyoshi Kon, Shunhei Yamashina, Kenichi Ikejima.
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2023 Taipei
  • Int'l Joint Research
• [Presentation] The trends of acute hepatitis A and hepatitis E during the COVID-19 pandemic in Japan. (2023)
  • Author(s): Hiroo Fukada, Kazuyoshi Kon, Satoshi Sakuma, Toshifumi Sato, Maki Morinaga, Toshifumi Yamagata, Akira Uchiyama, Reiko Yaginuma, Kyoko Fukuhara, Shunhei Yamashina, Kenichi Ikejima.
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) 2023 Taipei
  • Int'l Joint Research
• [Presentation] Type I and type II natural killar T cells are involved in the development of steatohepatitis in elder mice. (2022)
  • Author(s): Kazuyoshi Kon, Eisuke Nakadera, Kumiko Arai, Akira Uchiyama, Hiroo Fukada, Toshifumi Sato, Reiko Yaginuma, Kyoko Okumura, Shunhei Yamashina, Kenichi Ikejima.
  • Organizer: Digestive Disease Week 2022
  • Int'l Joint Research
• [Presentation] Glycine prevents steatohepatitis-related carcinogenesis in hepatocyte-specific phosphatase and tensin homolog-deficient mice. (2022)
  • Author(s): Kazuyoshi Kon, Kumiko Arai, Akira Uchiyama, Hiroo Fukada, Toshifumi Sato, Maki Morinaga, Kyoko Fukuhara, Reiko Yaginuma, Shunhei Yamashina, Kenichi Ikejima
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) Oncology 2022 Takamatsu
  • Int'l Joint Research
• [Presentation] Role of gut-liver axis and innate immunity in the pathogenesis of alcohol-related liver disease. (2022)
  • Author(s): Akira Uchiyama, Kenichi Ikejima
  • Organizer: The 2nd World Congress on Alcohol and Alcoholism, Cracow, Poland
  • Int'l Joint Research
• [Presentation] Glycine supplementation inhibits steatohepatitis-related liver carcinogenesis in hepaticyte-specific PTEN deficient mice. (2022)
  • Author(s): Kazuyoshi Kon, Kumiko Arai, Akira Uchiyama, Reiko Yaginuma, Toshifumi Sato, Shunhei Yamashina, Kenichi Ikejima
  • Organizer: American Association for the Study of Liver Disease (AASLD) The Liver Meeting 2022
  • Int'l Joint Research
• [Presentation] Perihepatitis and Fitz-Hugh-Curtis syndrome: an unusual condition for upper abdominal pain and liver injury? (2022)
  • Author(s): Akira Uchiyama, Kazuyoshi Kon, Hiroo Fukada, Maki Morinaga, Reiko Yaginuma, Kyoko Fukuhara, Shunhei Yamashina, Kenichi Ikejima.
  • Organizer: American Association for the Study of Liver Disease (AASLD) The Liver Meeting 2022
  • Int'l Joint Research
• [Presentation] Updates on pathogenesis of alcohol-associated liver disease (2022)
  • Author(s): Ikejima K
  • Organizer: the Asian Pcific Association for the Study of Liver (APASL) 2022 Seoul
  • Int'l Joint Research / Invited
• [Presentation] Hyperactivation of immune response following modulation of small intestinal microbiome causes exacerbation of alcoholic liver injury in female KK-Ay mice. (2021)
  • Author(s): K Kon, A Uchiyama, H Fukada, E Nakadera, R Yaginuma, K Fukuhara, S Yamashina, K Ikejima.
  • Organizer: 20th Congress of the International Society for Biomedical Research on Alcoholism
  • Int'l Joint Research
• [Presentation] Glycine ameliorates steatohepatitis via reduction of oxidative stress in hepatocyte-specific PTEN-deficient mice. (2021)
  • Author(s): K Kon, A Uchiyama, H Fukada, E Nakadera, R Yaginuma, K Fukuhara, S Yamashina, K Ikejima.
  • Organizer: The Asian Pacific Association for the Study of the Liver (APASL) Single Topic Conference. Molecular and Cell Biology of the Liver: Recent Evolution to Clinical Application, Osaka
  • Int'l Joint Research
• [Presentation] Type I and type II NKT cells additively exacerbates steatohepatitis caused by high-fat and high-cholesterol diet in aged mice. (2021)
  • Author(s): E Nakadera, K Kon, K Arai, H Fukada, A Uchiyama, S Yamashina, K Ikejima.
  • Organizer: American Association for the Study of Liver Disease (AASLD) The Liver Meeting
  • Int'l Joint Research
• [Presentation] Amino acid prevents tumorigenesis via ameliorating steatohepatitis in hepatocyte-specific phosphatase and tensin homolog knockout (2021)
  • Author(s): K Kon, K Arai, A Uchiyama, H Fukada, E Nakadera, M Morinaga, K Fukuhara, R Yaginuma, S Yamashina, K Ikejima.
  • Organizer: American Association for the Study of Liver Disease (AASLD) The Liver Meeting
  • Int'l Joint Research
• [Presentation] Accumulation of autophagy-specific substrate p62/SQSTM1 are associated with the formation of multinucleated cells in liver cancer (2021)
  • Author(s): S Yamashina, E Nakadera, H Fukada, A Uchiyama, R Yaginuma, K Fukuhra, K Kon, K Ikejima.
  • Organizer: American Association for the Study of Liver Disease (AASLD) The Liver Meeting
  • Int'l Joint Research