Molecular mechanisms and translational research in NASH and obesity-related liver cancer focusing on lipid metabolic reprograming

• Project/Area Number: 18H02789
• 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: The University of Tokyo
• Principal Investigator: Nakagawa Hayato 東京大学, 医学部附属病院, 助教 (00555609)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 非アルコール性脂肪肝炎 / 肝細胞癌 / アシルカルニチン / SREBP / 脂質代謝 / ビタミンD / 脂質生合成経路 / metabolic reprogramming / NASH

Outline of Final Research Achievements

We analzyed molecular mechanisms of NASH-related HCC development focusing on lipid metabolsim and explored biomarkers. In addition, we conducted preclinical studies using new compounds. We obtained the following results. 1) Altered serum acylcarnitine profile is a potential biomarker for NASH, 2) We developed VDR-silent vitamin D derivative that impairs SREBP in vivo, 3) Strong inhibition of SCAP-SREBP pawathy rather exacerbates liver injury in NASH, 4), Myeloid cell-specific KO of ASK1 prevents NASH-related HCC.

Academic Significance and Societal Importance of the Research Achievements

本研究結果によって、NASHの病態を反映する血清バイオマーカーを同定することができ、さらにNASHの治療につながり得る脂肪酸合成を標的とした新規化合物の導出に成功した。しかしながらマウスモデルにおける検討では、強力すぎる脂質生合成の阻害はかえってNASHの病態を悪化させる可能性を示唆する結果が得られた。このことは今後のNASHの治療戦略を考えるうえで、重要な示唆を与えるものである。

Research Products

• [Journal Article] Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging (2021)
  • Author(s): Nao Nagai, Yotaro Kudo, Daisuke Aki, Hayato Nakagawa, Koji Taniguchi
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 5 Pages: 2238-2238
  • DOI: 10.3390/ijms22052238
  • Peer Reviewed / Open Access
• [Journal Article] Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat. (2021)
  • Author(s): Matsushita Y, Nakagawa H, Koike K.
  • Journal Title: Cancers (Basel). Volume: 13 Issue: 3 Pages: 474-474
  • DOI: 10.3390/cancers13030474
  • Peer Reviewed / Open Access
• [Journal Article] Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma (2021)
  • Author(s): Nakatsuka T、Nakagawa H、Hayata Y、Wake T、Yamada T、Nishibatake Kinoshita M、Nakagmi R、Sato M、Minami T、Uchino K、Enooku K、Kudo Y、Tanaka Y、Kishikawa T、Otsuka M、Tateishi R、Koike K
  • Journal Title: Journal of Gastroenterology Volume: - Issue: 5 Pages: 01773-4
  • DOI: 10.1007/s00535-021-01773-4
  • Peer Reviewed
• [Journal Article] Discovery of a VDR-Silent Vitamin D Derivative That Impairs SREBP in Vivo. (2021)
  • Author(s): 1.Kawagoe F, Mendoza A, Hayata Y, Asano L, Kotate K, Mototani S, Kawamura S, Kurosaki S, Akagi Y, Takemoto Y, Nagasawa K, Nakagawa H, Uesugi M, Kittaka A.
  • Journal Title: J Med Chem. Volume: in press
  • Peer Reviewed
• [Journal Article] Altered serum acylcarnitine profile is associated with the status of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related hepatocellular carcinoma (2019)
  • Author(s): Enooku Kenichiro、Nakagawa Hayato、Fujiwara Naoto、Kondo Mayuko、Minami Tatsuya、Hoshida Yujin、Shibahara Junji、Tateishi Ryosuke、Koike Kazuhiko
  • Journal Title: Scientific Reports Volume: 9 Issue: 1
  • DOI: 10.1038/s41598-019-47216-2
  • Peer Reviewed / Open Access
• [Journal Article] Lipid Metabolic Reprogramming in Hepatocellular Carcinoma. (2018)
  • Author(s): Nakagawa H, Hayata Y, Kawamura S, Yamada T, Fujiwara N, Koike K.
  • Journal Title: Cancers Volume: 10 Issue: 11 Pages: 447-447
  • DOI: 10.3390/cancers10110447
  • Peer Reviewed / Open Access
• [Presentation] ケミカルバイオロジーに基づくNAFLDに対する新規治療法の創出；人工ビタミンD誘導体による脂肪肝抑制効果 (2020)
  • Author(s): 中川勇人、小池和彦
  • Organizer: 第56回肝臓学会総会
• [Presentation] Inhibition of SCAP/SREBP-mediated lipogenesis exacerbates liver injury in murine NASH model via disturbance of phospholipid metabolism. (2020)
  • Author(s): Kawamura S, Nakagawa H, Koike K
  • Organizer: JDDW2020
• [Presentation] NASH病態進展における脂質生合成経路の役割 (2019)
  • Author(s): 川村聡、中川勇人、小池和彦
  • Organizer: 第27回JDDW
• [Presentation] 2.Clinical applications of liquid biopsy as a novel biomarker in hepatocellular carcinoma. (2019)
  • Author(s): Takuma Nakatsuka, Hayato Nakagawa, Kazuhiko Koike
  • Organizer: JDDW International Session
• [Presentation] 3.NASH・肥満関連肝癌に特異的な脂質代謝リプログラミングに基づく病態解明とバイオマーカー探索 (2019)
  • Author(s): 中川勇人、小池和彦
  • Organizer: 第55回肝臓学会総会
• [Presentation] 4.Metabolic reprogramming in hepatocellular carcinoma for adaptation to lipid-rich environment. (2019)
  • Author(s): Hayato Nakagawa
  • Organizer: JSH-EASL Joint Session
• [Presentation] NASH・肥満関連肝癌におけるlipid metabolic reprogramming (2019)
  • Author(s): 中川勇人、小池和彦
  • Organizer: 第6回肝臓と糖尿病・代謝研究会
  • Invited
• [Presentation] 癌種特異的脂質代謝リプログラミングを標的とした新規治療戦略 (2018)
  • Author(s): 中川勇人、小池和彦
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
  • Invited
• [Presentation] NAFLD患者241症例における血清アシルカルニチン精密分析 (2018)
  • Author(s): 中川勇人、榎奥健一郎、小池和彦
  • Organizer: 酸化ストレスと肝研究会
• [Patent(Industrial Property Rights)] 3.ＮＡＦＬＤ又はＮＡＳＨの検出又はリスクの予測方法、ＮＡＦＬＤ又はＮＡＳＨを検出するための診断薬キット (2018)
  • Inventor(s): 中川勇人
  • Industrial Property Rights Holder: 中川勇人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2019
• [Patent(Industrial Property Rights)] 4.脂肪性肝疾患の検出又はリスクの予測方法、脂肪性肝疾患を検出するための診断薬キット及びバイオマーカー (2018)
  • Inventor(s): 中川勇人
  • Industrial Property Rights Holder: 中川勇人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2019
• [Patent(Industrial Property Rights)] 脂肪性肝疾患の検出又はリスクの予測方法、脂肪性肝疾患を検出するための診断薬キット (2018)
  • Inventor(s): 中川勇人、榎奥健一郎、藤原直人、小池和彦、曲尾直樹、青木泰仁
  • Industrial Property Rights Holder: 中川勇人、榎奥健一郎、藤原直人、小池和彦、曲尾直樹、青木泰仁
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas
• [Patent(Industrial Property Rights)] ＮＡＦＬＤ又はＮＡＳＨの検出又はリスクの予測方法、ＮＡＦＬＤ又はＮＡＳＨを検出するための診断薬キット及び対象における肝線維化の進行度を判定するための診断薬キット (2018)
  • Inventor(s): 中川勇人、榎奥健一郎、藤原直人、小池和彦、曲尾直樹、青木泰仁
  • Industrial Property Rights Holder: 中川勇人、榎奥健一郎、藤原直人、小池和彦、曲尾直樹、青木泰仁
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas