Fatty acid metabolic system that controls thepathophysiology of steatohepatitis

• Project/Area Number: 19H03643
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokai University
• Principal Investigator: KAMIYA AKIHIDE 東海大学, 医学部, 准教授 (30321904)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 肝細胞 / 非アルコール性脂肪肝炎 / iPS細胞 / 脂肪性肝炎 / Bcl6 / NASH / 肝臓 / 脂肪肝炎 / 脂質代謝 / 病態モデルマウス

Outline of Research at the Start

肥満等のメタボリックシンドロームは、肝臓では脂肪の過剰蓄積に伴う脂肪肝や非アルコール性脂肪肝炎（NASH）を引き起こし、肝硬変・肝癌といった重篤な疾患につながる。我々は、肝細胞における特定の転写調節因子の発現が脂肪酸代謝酵素などを制御しつつ、NASH誘導性肝障害や発癌に重要なことを既に見出している。
そこで本研究では、この転写調節因子をNASH発癌の新規治療ターゲットと考え、特に肝臓内脂肪酸の蓄積量や質の調節機能に着目し新規創薬につながるような研究を推進する。

Outline of Final Research Achievements

The liver is an important organ for fatty acid metabolism, and the progression of metabolic syndrome leads to non-alcoholic steatohepatitis, liver tumors, and the like. We have found that Bcl6, one of the transcription factors that control liver function, is involved in the pathological control of steatohepatitis. Therefore, in this study, we analyzed the function of downstream factors of Bcl6 using an in vivo rapid gene deletion induction system using adeno-associated virus and genome editing enzyme. We also constructed an in vitro steatohepatitis induction system using human iPS cell-derived hepatocytes.

Academic Significance and Societal Importance of the Research Achievements

本研究では、我々が見出した脂肪肝炎制御因子としてのBcl6の機能に着目し、その下流因子と病態との関連について解析した。Bcl6の下流で脂肪肝炎の病態を悪化させる可能性のある因子を複数同定しており、今後これらの因子の活性を阻害するような薬剤を見出すことで、現在増加しつつある非アルコール性脂肪肝炎の治療等に役立つと考えている。

Research Products

• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] the McGill University Health Center(カナダ)
• [Journal Article] Kruppel-like factor 15 induces the development of mature hepatocyte-like cells from hepatoblasts (2021)
  • Author(s): Anzai Kazuya、Tsuruya Kota、Ida Kinuyo、Kagawa Tatehiro、Inagaki Yutaka、Kamiya Akihide
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 18551-18551
  • DOI: 10.1038/s41598-021-97937-6
  • Peer Reviewed / Open Access
• [Journal Article] Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver (2021)
  • Author(s): AlOgayil Najla、Bauermeister Klara、Galvez Jose Hector、Venkatesh Varun S.、Zhuang Qinwei Kim-wee、Chang Matthew L.、Davey Rachel A.、Zajac Jeffrey D.、Ida Kinuyo、Kamiya Akihide、Taketo Teruko、Bourque Guillaume、Naumova Anna K.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 13766-13766
  • DOI: 10.1038/s41598-021-93216-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ammonia-based enrichment and long-term propagation of zone I hepatocyte-like cells (2021)
  • Author(s): Tsuneishi Ruri、Saku Noriaki、Miyata Shoko、Akiyama Saeko、Javaregowda Palaksha Kanive、Ite Kenta、Takashima Nagisa、Toyoda Masashi、Kimura Tohru、Kuroda Masahiko、Nakazawa Atsuko、Kasahara Mureo、Nonaka Hidenori、Kamiya Akihide、Kiyono Tohru、Yamauchi Junji、Umezawa Akihiro
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 11381-11381
  • DOI: 10.1038/s41598-021-90708-3
  • Peer Reviewed / Open Access
• [Journal Article] Bile duct reconstruction using scaffold-free tubular constructs created by Bio-3D printer. (2021)
  • Author(s): Takashi Hamada, Anna Nakamura, Akihiko Soyama, Yusuke Sakai, Takayuki Miyoshi, Shun Yamaguchi, Masaaki Hidaka, Takanobu Hara, Tota Kugiyama, Mitsuhisa Takatsuki, Akihide Kamiya, Koichi Nakayama, Susumu Eguchi.
  • Journal Title: Regenerative Therapy Volume: 16 Pages: 81-89
  • DOI: 10.1016/j.reth.2021.02.001
  • Peer Reviewed / Open Access
• [Journal Article] Visualization and isolation of zone-specific murine hepatocytes that maintain distinct cytochrome P450 oxidase expression in primary culture (2020)
  • Author(s): Kasahara Daigo、Sumiyoshi Hideaki、Endo Hitoshi、Yanagawa Takayo、Nakano Yasuhiro、Matsuki Yuki、Nakao Sachie、Kamiya Akihide、Kimura Hiroshi、Inagaki Yutaka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 528 Issue: 3 Pages: 420-425
  • DOI: 10.1016/j.bbrc.2020.05.202
  • Peer Reviewed / Open Access
• [Journal Article] Liver-specific knockout of B cell lymphoma 6 suppresses progression of non-alcoholic steatohepatitis in mice (2020)
  • Author(s): Chikada Hiromi、Ida Kinuyo、Nishikawa Yuji、Inagaki Yutaka、Kamiya Akihide
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 9704-9704
  • DOI: 10.1038/s41598-020-66539-z
  • Peer Reviewed / Open Access
• [Journal Article] Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts (2020)
  • Author(s): Sato A, Kakinuma S, Miyoshi M, Kamiya A, Tsunoda T, Kaneko S, Tsuchiya J, Shimizu T, Takeichi E, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Koshikawa N, Seiki S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Hepatology Communications Volume: 4 Issue: 2 Pages: 235-254
  • DOI: 10.1002/hep4.1459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Fibrocystin Promotes Interleukin-8-Dependent Proliferation and CTGF Production of Biliary Epithelium. (2019)
  • Author(s): Tsunoda T, Kakinuma S, Miyoshi M, Kamiya A, Kaneko S, Sato A, Tsuchiya J, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Sogo T, Komatsu H, Mukouchi R, Inui A, Fujisawa T, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Journal of Heptatology Volume: 印刷中 Issue: 1 Pages: 143-152
  • DOI: 10.1016/j.jhep.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. (2019)
  • Author(s): Miyoshi M, Kakinuma S, Kamiya A, Tsunoda T, Tsuchiya J, Sato A, Kaneko S, Nitta S, Kawai-Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Asahina Y, Watanabe M.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2072-2072
  • DOI: 10.1038/s41598-018-37430-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 転写抑制因子Bcl6を介した非アルコール性脂肪肝炎を制御する新規メカニズムの解明 (2021)
  • Author(s): 紙谷聡英、近田裕美、井田絹代
  • Organizer: 第7回肝臓と糖尿病・代謝研究会
• [Presentation] 肝臓の性差制御因子を介した非アルコール性脂肪肝炎の病態変化 (2021)
  • Author(s): 紙谷聡英
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] ヒトiPS細胞由来肝前駆細胞の増殖・成熟化を制御する内在性因子の探索 (2020)
  • Author(s): 紙谷聡英
  • Organizer: 第19回日本再生医療学会
• [Presentation] Maturation of hepatic progenitor cells regulated by Kruppel-like transcription factors (2019)
  • Author(s): Akihide Kamiya
  • Organizer: CSH Asia Liver conference
  • Int'l Joint Research
• [Remarks] 東海大・医・紙谷聡英研究室
  • URL: https://akihkamiya.wixsite.com/tokai-u-kamiya-lab