Innate immune regulation in metabolic steatohepatitis and experimental therapeutics

• Project/Area Number: 15K09023
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Juntendo University
• Principal Investigator: Ikejima Kenichi 順天堂大学, 医学部, 教授 (20317382)
• Co-Investigator(Kenkyū-buntansha): 山科 俊平 順天堂大学, 医学部, 准教授 (30338412) ; 今 一義 順天堂大学, 医学部, 准教授 (30398672)
• Co-Investigator(Renkei-kenkyūsha): TAKEDA Kazuyoshi 順天堂大学, 医学(系)研究科(研究院), 准教授 (80272821)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 非アルコール性脂肪肝炎（NASH） / 自然免疫 / NKT細胞 / 腸内マイクロバイオーム / アミノ酸 / 免疫栄養 / 耐糖能異常 / 非アルコール性脂肪肝炎（NASH) / 糖代謝 / インスリン / 腸内細菌叢 / RIG-I / メタボリックシンドローム

Outline of Final Research Achievements

In this study, we investigated the role of innate immune responses in metabolic steatohepatitis (MetSH), and evaluate the protective effect of amino acid on MetSH.In MetSH model KK-Ay mice, glycine ameliorated glucose intolerance, accompanied with changes in gut microbiota. Progressive depletion of hepatic NK and NKT cells, in combination with increases in myeloid suppressor cells, were observed in hepatocyte-specific Pten-KO mice, which spontaneously develop steatohepatitis and hepatocellular adenoma/carcinoma upon aging. Glycine also prevented steatohepatitis and tumorigenesis in Pten-KO mice. These findings clearly indicated that pharmaco-nutritional approach utilizing glycine is promising for prevention and treatment of MetSH including MetSH-related carcinogenesis.

Research Products

• [Journal Article] Formation of p62-positive inclusion body is associated with macrophage polarization in non-alcoholic fatty liver disease. (2018)
  • Author(s): Fukushima H, Yamashina S, Arakawa A, Taniguchi G, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S.
  • Journal Title: Hepatol Res. Volume: 48 Issue: 9 Pages: 757-767
  • DOI: 10.1111/hepr.13071
  • Peer Reviewed
• [Journal Article] Progress in research of NASH (2018)
  • Author(s): 渡辺純夫，今一義，池嶋健一
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 115 Issue: 1 Pages: 1-9
  • DOI: 10.11405/nisshoshi.115.1
  • NAID: 130006316870
  • ISSN: 0446-6586, 1349-7693
  • Peer Reviewed
• [Journal Article] A Customized Online Nutrition Guidance System Is Effective for Treating Patients with Nonalcoholic Fatty Liver Disease by Supporting Continuity of Diet Therapy at Home: A Pilot Study (2017)
  • Author(s): Aoyama T, Takada H, Uchiyama A, Kon K, Yamashina S, Ikejima K, Ban H, Watanabe S.
  • Journal Title: Internal Medicine Volume: 56 Issue: 13 Pages: 1651-1656
  • DOI: 10.2169/internalmedicine.56.8187
  • NAID: 130006858091
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Spleen-derived lipocalin-2 in the portal vein regulates Kupffer cells activation and attenuates the development of liver fibrosis in mice. (2017)
  • Author(s): Aoyama T, Kuwahara-Arai K, Uchiyama A, Kon K, Okubo H, Yamashina S, Ikejima K, Kokubu S, Miyazaki A, Watanabe S.
  • Journal Title: Lab Invest. Volume: 97 Issue: 8 Pages: 890-902
  • DOI: 10.1038/labinvest.2017.44
  • Peer Reviewed
• [Journal Article] Sodium 4-phenylbutyric acid prevents murine acetaminophen hepatotoxicity by minimizing endoplasmic reticulum stress. (2017)
  • Author(s): Kusama H, Kon K, Ikejima K, Arai K, Aoyama T, Uchiyama A, Yamashina S, Watanabe S.
  • Journal Title: J Gastroenterol. Volume: 52 Issue: 5 Pages: 611-622
  • DOI: 10.1007/s00535-016-1256-3
  • Peer Reviewed / Open Access
• [Journal Article] L-carnitine prevents metabolic steatohepatitis in obese diabetic KK-Ay mice. (2016)
  • Author(s): Kon K, Ikejima K, Morinaga M, Kusama H, Arai K, Aoyama T, Uchiyama A, Yamashina S, Watanabe S
  • Journal Title: Hepatology Research Volume: Apr Issue: 3 Pages: 44-54
  • DOI: 10.1111/hepr.12720
  • Peer Reviewed / Open Access
• [Journal Article] Glycine prevents metabolic steatohepatitis in diabetic KK-Ay mice through modulation of hepatic innate immunity. (2016)
  • Author(s): Takashima S, Ikejima K, Arai K, Yokokawa J, Kon K, Yamashina S, Watanabe S.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 311 Issue: 6 Pages: G1105-G1113
  • DOI: 10.1152/ajpgi.00465.2015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis. (2016)
  • Author(s): Nakadera E, Yamashina S, Izumi K, Inami Y, Sato T, Fukushima H, Kon K, Ikejima K, Ueno T, Watanabe S.
  • Journal Title: Biochem Biophys Res Commun Volume: 469(4) Issue: 4 Pages: 1104-10
  • DOI: 10.1016/j.bbrc.2015.12.010
  • Peer Reviewed
• [Journal Article] Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. (2015)
  • Author(s): Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M,
  • Journal Title: J Gastroenterol Volume: 50(4) Issue: 4 Pages: 364-377
  • DOI: 10.1007/s00535-015-1050-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sodium 4-phenylbutyrate prevents murine dietary steatohepatitis caused by <i>trans</i>-fatty acid plus fructose (2015)
  • Author(s): Morinaga M, Kon K, Saito H, Arai K, Kusama H, Uchiyama A, Yamashina S, Ikejima K, Watanabe S.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 57 Issue: 3 Pages: 183-191
  • DOI: 10.3164/jcbn.15-75
  • NAID: 130005106455
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Presentation] Female hormone enhances hepatic innate and autoimmune responses against double-stranded RNA. (2017)
  • Author(s): Uchiyama A, Ikejima K, Someya S, Arai K, Aoyama T, Kon K, Yamashina S, Watanabe S.
  • Organizer: the Liver Meeting 2017 (AASLD)
  • Int'l Joint Research
• [Presentation] Aging exacerbates high-fat diet-induced steatohepatitis through blunting of lipid metabolic response in mice. (2017)
  • Author(s): Ishizuka K, Kon K, Ikejima K, Suzuki M, Arai K, Uchiyama A, Aoyama T, Yamashina S, Watanabe S.
  • Organizer: the Liver Meeting 2017 (AASLD)
  • Int'l Joint Research
• [Presentation] L-carnitine changes hepatic lipid composition and prevents lipotoxicity in hign-fat diet-fed KK-Ay mice. (2017)
  • Author(s): Kon K, Ikejima K, Uchiyama A, Arai K, Aoyama T, Yamashina S, Watanabe S.
  • Organizer: Digestive Disease Week
  • Int'l Joint Research
• [Presentation] Glycine minimizes murine autoimmune cholangitisand pancreatitis caused by double-stranded RNA through modulation of innate immune response. (2017)
  • Author(s): Uchiyama A, Ikejima K, Kon K, Arai K, Fukuhara K, Aoyama T, Yamashina S, Watanabe S 演題名 GLYCINE MINIMIZES MURINE AUTOIMMUNE CHOLANGITIS AND PANCREATITIS CAUSED BY DOUBLE-STRANDED RNA THROUGH MODULATION OF INNATE IMMUNE RESPONSES 学会名
  • Organizer: Digestive Disease Week
  • Int'l Joint Research
• [Presentation] The formation of P62-positive inclusion body is associated with macrophage polarization in non-alcohoic fatty liver disease. (2017)
  • Author(s): Fukushima H, Yamashina S, Arakawa A, Taniguchi G, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S.
  • Organizer: Digestive Disease Week
  • Int'l Joint Research
• [Presentation] Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA (2016)
  • Author(s): Someya S, Ikejima K, Uchiyama A, Arai K, Kon K, Aoyama T, Yamasina S, Watanabe S
  • Organizer: The Liver Meeting 2016 (AASLD)
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Efficacy of denosumab on progression of osteoporosis in autoimmune liver diseases (2016)
  • Author(s): Ikejima K, Yaginuma R, Kon K, Aoyama T, Uchiyama A, Yamashina S, Watanabe S
  • Organizer: The Liver Meeting 2016 (AASLD)
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] 自己免疫性胆管病変マウスモデルにおける性差の解析 (2016)
  • Author(s): 染谷秀忍，池嶋健一，内山明，鈴木麻衣子，青山友則，今一義，山科俊平，渡辺純夫
  • Organizer: JDDW2016
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03
• [Presentation] Real-world efficacy of antiviral treatment using a combination of daclatasvir and asnaprevir in Japanese patients of chronic hepatitis C (2016)
  • Author(s): Ikejima K, Fukuhara K, Aoyama T, Uchiyama A, Kon K, Yamashina S, Watanabe S
  • Organizer: HCV2016
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] NAFLD・NASHの病態形成と自然免疫 (2016)
  • Author(s): 池嶋健一
  • Organizer: 第53回日本消化器免疫学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2016-07-14
  • Invited
• [Presentation] Metabolic disease and NASH (2016)
  • Author(s): Ikejima K, Kon K, Yamashina S, Watanabe S
  • Organizer: 25th Conference of the Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Tokyo
  • Year and Date: 2016-02-23
  • Int'l Joint Research / Invited
• [Presentation] Contribution of regulatory T cells in pathogenesis of nonalcoholic steatohepatitis in mice (2015)
  • Author(s): Ikejima K, Yokokawa J, Arai K, Uchiyama A, Kon K, Yamashina S, Watanabe S
  • Organizer: 18th International Symposium on the Cells of Hepatic Sinusoid
  • Place of Presentation: Asilomar, CA, USA
  • Year and Date: 2015-11-11
  • Int'l Joint Research
• [Presentation] Immuno-nutritional approach for impaired glucose tolerance in metabolic steatohepatitis through modulation of Kupffer cell function (2015)
  • Author(s): Ikejima K, Kon K, Watanabe S
  • Organizer: 第23回日本消化器関連学会週間（JDDW）
  • Place of Presentation: Tokyo
  • Year and Date: 2015-10-09
• [Presentation] Steatohepatitis syndromeの共通病態基盤としてのKupffer細胞極性変化と免疫栄養的制御 (2015)
  • Author(s): 池嶋健一，今一義，渡辺純夫
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-22
• [Presentation] Dietary glycine improves impaired glucose tolerance by modulating polarization of Kupffer cells in diabetic KK-Ay mice. (2015)
  • Author(s): Ikejima K, Arai K, Kon K, Uchiyama A, Yamashina S, Watanabe S
  • Organizer: Digestive Disease Week
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2015-05-17
  • Int'l Joint Research