Study of the role of the vagal liver branch in the onset and progression mechanism of nonalcoholic steatohepatitis.

• Project/Area Number: 18K08014
• 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: Keio University
• Principal Investigator: TERATANI Toshiaki 慶應義塾大学, 医学部(信濃町), 講師 (40624408)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 非アルコール性脂肪肝炎 / 脳肝相関 / 肝星細胞 / 肝臓病 / 臓器相関 / 迷走神経 / 肝臓星細胞 / 肝臓線維化 / 副交感神経 / 非アルコール性脂肪性肝炎 / 神経細胞 / 迷走神経肝臓枝

Outline of Final Research Achievements

Non-alcoholic steatohepatitis (NASH) is a phenotype of lifestyle-related disease in the liver. NASH is a disease that progresses to cirrhosis and eventually hepatocellular carcinoma. In Japan, where the number of NASH patients is increasing rapidly, it is necessary to elucidate the pathogenesis and progression mechanism of NASH. Therefore, in this study, we aimed to elucidate the role of the hepatic vagal branch in NASH pathology.
Resection of the hepatic vagal branch exacerbated the liver fibrotic pathology of MCD-NASH. Analysis of neurotransmitter receptor gene expression in hepatic stellate cells revealed high expression of muscarinic acetylcholine receptor subtype 2 (mAchR2). In mAchR2-deficient mice, CCl4 or MCD-induced liver fibrosis was even exacerbated compared to wild-type mice. It was suggested that the muscarinic signal in hepatic stellate cell has an inhibitory effect on liver fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、近年注目される脳肝相関に着目した。肝臓内の神経線維維持において、肝星細胞が分泌されるグリア細胞株由来神経栄養因子が重要な役割を果たすことが本研究により明らかとされた。さらに、肝星細胞内のムスカリンシグナルが活性化および細胞増殖を抑制していることが明らかとなった。これまで、脳からの指令は、肝細胞や免疫細胞に作用することが示されてきたが、本研究により脳から伝播されるシグナルは肝星細胞のような線維芽細胞にも作用することが示された。

Research Products

• [Journal Article] Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling (2020)
  • Author(s): Teratani Toshiaki、Tomita Kengo、Toma-Fukai Sachiko、Nakamura Yutaro、Itoh Toshimasa、Shimizu Hikaru、Shiraishi Yasunaga、Sugihara Nao、Higashiyama Masaaki、Shimizu Takahiko、Inoue Ikuo、Takenaka Yasuhiro、Hokari Ryota、Adachi Takeshi、Shimizu Toshiyuki、Miura Soichiro、Kanai Takanori
  • Journal Title: Free Radical Biology and Medicine Volume: 156 Pages: 45-56
  • DOI: 10.1016/j.freeradbiomed.2020.06.005
  • Peer Reviewed / Open Access
• [Journal Article] Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study. (2020)
  • Author(s): Naganuma M, Sugimoto S, Fukuda T, Mitsuyama K, Kobayashi T, Yoshimura N, Ohi H, Tanaka S, Andoh A, Ohmiya N, Saigusa K, Yamamoto T, Morohoshi Y, Ichikawa H, Matsuoka K, Hisamatsu T, Watanabe K, Mizuno S, Abe T, Suzuki Y, Kanai T; INDIGO Study Group.
  • Journal Title: J Gastroenterol. Volume: 55 Issue: 2 Pages: 169-180
  • DOI: 10.1007/s00535-019-01625-2
  • Peer Reviewed / Open Access
• [Journal Article] Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. (2019)
  • Author(s): Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T.
  • Journal Title: Hepatol Commun. Volume: 6 Issue: 8 Pages: 1098-1112
  • DOI: 10.1002/hep4.1383
  • Peer Reviewed
• [Journal Article] Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. (2019)
  • Author(s): Koda Y, Nakamoto N, Chu P, Ugamura A, Teratani T, Shiba S, Taniki N, Sujino T, Miyamoto K, Mikami Y, Suzuki T, Yamaguchi A, Morikawa R, Sato K, Yoshimoto T, Kanai K.
  • Journal Title: J Clin Invest Volume: 129(8) Issue: 8 Pages: 3201-3213
  • DOI: 10.1172/jci125863
  • Peer Reviewed / Open Access
• [Journal Article] Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. (2019)
  • Author(s): Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, Suzuki T, Koda Y, Chu PS, Taniki N, Yamaguchi A, Kanamori M, Kamada N, Hattori M, Ashida H, Sakamoto M, Atarashi K, Narushima S, Yoshimura A, Honda K, Sato T, Kanai T.
  • Journal Title: Nat Microbiol. Volume: 4 Issue: 3 Pages: 492-503
  • DOI: 10.1038/s41564-018-0333-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll-Like Receptor 7 Agonist-Induced Dermatitis Causes Severe Dextran Sulfate Sodium Colitis by Altering the Gut Microbiome and Immune Cells. (2018)
  • Author(s): Kiyohara H, Sujino T, Teratani T, Miyamoto K, Arai MM, Nomura E, Harada Y, Aoki R, Koda Y, Mikami Y, Mizuno S, Naganuma M, Hisamatsu T, Kanai T.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 7 Issue: 1 Pages: 135-156
  • DOI: 10.1016/j.jcmgh.2018.09.010
  • Peer Reviewed / Open Access
• [Journal Article] Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells. (2018)
  • Author(s): Murakami Y, Sugiyama K, Ebinuma H, Nakamoto N, Ojiro K, Chu PS, Taniki N, Saito Y, Teratani T, Koda Y, Suzuki T, Saito K, Fukasawa M, Ikeda M, Kato N, Kanai T, Saito H.
  • Journal Title: BMC Cancer. Volume: 3 Issue: 1 Pages: 680-680
  • DOI: 10.1186/s12885-018-4588-y
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages. (2018)
  • Author(s): Taniki N, Nakamoto N, Chu PS, Mikami Y, Amiya T, Teratani T, Suzuki T, Tsukimi T, Fukuda S, Yamaguchi A, Shiba S, Miyake R, Katayama T, Ebinuma H, Kanai T.
  • Journal Title: JCI Insight. Volume: 3 Issue: 12
  • DOI: 10.1172/jci.insight.91980
  • Peer Reviewed / Open Access
• [Journal Article] Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis. (2018)
  • Author(s): Teratani T, Tomita K, Suzuki T, Furuhashi H, Irie R, Nishikawa M, Yamamoto J, Hibi T, Miura S, Minamino T, Oike Y, Hokari R, and Kanai T.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 4 Pages: 1581-1596
  • DOI: 10.1172/jci92863
  • Peer Reviewed / Open Access