Elucidation of the pathological mechanism of obesity-related liver cancer and development of the new treatment methods, focusing on secretory factors from hepatic stellate cells

• Project/Area Number: 18K07924
• 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: National Defense Medical College
• Principal Investigator: Tomita Kengo 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 病院 内科, 准教授 (50317129)
• 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: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 非アルコール性脂肪肝炎 / 肝臓がん / 肝線維化 / 肝星細胞 / lipoprotein lipase / 肝がん / 肥満 / ACLP / Wnt / β-カテニン

Outline of Final Research Achievements

In patients with nonalcoholic steatohepatitis (NASH), increased secretion of lipoprotein lipase (LPL) was observed specifically in hepatic stellate cells (HSCs). The increase in serum obesity-related factors, associated with NASH, promoted LPL secretion in HSCs. LPL enhanced cholesterol uptake from serum lipoproteins into HSCs and promoted free cholesterol accumulation in HSCs, resulting in activation of HSCs via TLR4 signal enhancement and progression of liver fibrosis in NASH. These results also suggest that LPL could be involved in the pathophysiology of obesity-related liver cancer.

Academic Significance and Societal Importance of the Research Achievements

NASHの患者数は本邦で300万人にも達するとされているものの、未だ確立された治療法が存在しない。本研究により、肝星細胞由来の分泌因子LPL がNASH肝線維化を進展させることが明らかとなった。今後LPLを標的とすることにより、患者数の多いNASHおよびそれに伴う肥満関連肝がんの新たな治療法を確立できる可能性が高く、本研究成果の学術的・社会的意義は大きい。

Research Products

• [Journal Article] T1ρ magnetic resonance imaging value as a potential marker to assess the severity of liver fibrosis: A pilot study (2021)
  • Author(s): Suyama Yohsuke、Tomita Kengo、Soga Shigeyoshi、Kuwamura Hiroshi、Murakami Wakana、Hokari Ryota、Shinmoto Hiroshi
  • Journal Title: European Journal of Radiology Open Volume: 8 Pages: 100321-100321
  • DOI: 10.1016/j.ejro.2021.100321
  • Peer Reviewed
• [Journal Article] Protective Effect of Luminal Uric acid Against Indomethacin-induced Enteropathy: Role of Antioxidant Effect and Gut Microbiota (2021)
  • Author(s): Wada A; Higashiyama M.; Kurihara C.; Ito S.; Tanemoto R.; Mizoguchi A.; Nishii S.;Inaba K.; Sugihara N.; Hanawa .Y; Horiuchi K.; Shibuya N.; Akiyama M.; Okada Y.; Watanabe C.; Komoto S.; Tomita K.; Takei F.; Hokari R.
  • Journal Title: Digestive Diseases and Sciences. Volume: in press Issue: 1 Pages: 121-133
  • DOI: 10.1007/s10620-021-06848-z
  • Peer Reviewed
• [Journal Article] Intestinal inflammations increase efflux of innate lymphoid cells from the intestinal mucosa to the mesenteric lymph nodes through lymph-collecting ducts (2021)
  • Author(s): Kazuki Horiuchi, Masaaki Higashiyama, Chie Kurihara, Kouji Matsumura, Rina Tanemoto, Suguru Ito, Akinori Mizoguchi, Shin Nishii, Akinori Wada, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Kengo Tomita, Ryota Hokari
  • Journal Title: Microcirculation Volume: - Issue: 5
  • DOI: 10.1111/micc.12694
  • Peer Reviewed
• [Journal Article] Deoxycholic acid enhancement of lymphocyte migration through direct interaction with the intestinal vascular endothelium (2021)
  • Author(s): Shibuya N、Higashiyama M、Akita Y、Shirakabe K、Ito S、Nishii S、Mizoguchi A、Inaba K、Tanemoto R、Sugihara N、Hanawa Y、Wada A、Horiuchi K、Yoshikawa K、Kurihara C、Okada Y、Watanabe C、Komoto S、Tomita K、Saruta M、Hokari R
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 9 Pages: 2523-2530
  • DOI: 10.1111/jgh.15509
  • Peer Reviewed
• [Journal Article] Associations among liver disease, serum lipid profile, body mass index, ketonuria, meal skipping, and the alcohol dehydrogenase‐1B and aldehyde dehydrogenase‐2 genotypes in Japanese men with alcohol dependence (2020)
  • Author(s): Yokoyama Akira、Taniki Nobuhito、Nakamoto Nobuhiro、Tomita Kengo、Hara Sachiko、Mizukami Takeshi、Maruyama Katsuya、Yokoyama Tetsuji
  • Journal Title: Hepatology Research Volume: 50 Issue: 5 Pages: 565-577
  • DOI: 10.1111/hepr.13475
  • Peer Reviewed
• [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] Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone? (2020)
  • Author(s): Sumida Y、Yoneda M、Toyoda H、Yasuda S、Tada T、Hayashi H、Nishigaki Y、Suzuki Y、Naiki T、Morishita A、Tobita H、Sato S、Kawabe N、Fukunishi S、Ikegami T、Kessoku T、Ogawa Y、Honda Y、Nakahara T、Munekage K、Ochi T、Sawada K、Takahashi A、Arai T、Kogiso T、Kimoto S、Tomita K., et al.
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 14 Pages: 4939-4939
  • DOI: 10.3390/ijms21144939
  • Peer Reviewed
• [Journal Article] Repeat Balloon-Occluded Retrograde Transvenous Obliteration for Recurrent Gastric Varices via the Left Inferior Phrenic Vein (2020)
  • Author(s): Suyama Yohsuke、Yamada Kentaro、Tsuda Masaki、Tomita Kengo、Shinmoto Hiroshi
  • Journal Title: Journal of Vascular and Interventional Radiology Volume: 31 Issue: 11 Pages: 1914-1916.e1
  • DOI: 10.1016/j.jvir.2020.06.022
  • Peer Reviewed
• [Journal Article] Angiopoietin-like protein 4 deficiency augments liver fibrosis in liver diseases such as nonalcoholic steatohepatitis in mice through enhanced free cholesterol accumulation in hepatic stellate cells. (2020)
  • Author(s): Teratani T., Tomita K., Wada A., Sugihara N., Higashiyama M., Inaba K., Horiuchi K., Hanawa Y., Nishii S., Mizoguchi A., Tanemoto R., Ito S., Okada Y., Kurihara C., Akita Y., Narimatsu K., Watanabe C., Komoto S., Oike Y., Miura S., Hokari R., Kanai T.
  • Journal Title: Hepatol Res Volume: - Issue: 5 Pages: 580-592
  • DOI: 10.1111/hepr.13603
  • Peer Reviewed / Open Access
• [Journal Article] Depression Promotes the Onset of Irritable Bowel Syndrome through Unique Dysbiosis in Rats. (2019)
  • Author(s): Takajo T, Tomita K, Tsuchihashi H, Enomoto S, Tanichi M, Toda H, Okada Y, Furuhashi H, Sugihara N, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Shirakabe K, Higashiyama M, Kurihara C, Watanabe C, Komoto S, Nagao S, Kimura K, Miura S, Shimizu K, Hokari R.
  • Journal Title: Gut and Liver Volume: 印刷中 Issue: 3 Pages: 325-332
  • DOI: 10.5009/gnl18296
  • Peer Reviewed
• [Journal Article] Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine-1-phosphate lyase inhibitor. (2019)
  • Author(s): Shirakabe K, Higashiyama M, Furuhashi H, Takajo T, Maruta K, Okada Y, Kurihara C, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Saruta M, Hokari R.
  • Journal Title: J Gastroenterol Hepatol. Volume: 印刷中 Issue: 9 Pages: 1608-1616
  • DOI: 10.1111/jgh.14092
  • Peer Reviewed
• [Journal Article] Nicotine treatment ameliorates DSS-induced colitis by suppressing MAdCAM-1 expression and leukocyte recruitment. (2018)
  • Author(s): Maruta K, Watanabe C, Hozumi H, Kurihara C, Furuhashi H, Takajo T, Okada Y, Shirakabe K, Higashiyama M, Komoto S, Tomita K, Nagao S, Ishizuka T, Miura S, Hokari R.
  • Journal Title: J Leukoc Biol Volume: 104 Issue: 5 Pages: 1013-1022
  • DOI: 10.1002/jlb.3a0717-304r
  • Peer Reviewed
• [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
• [Journal Article] Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis. (2018)
  • Author(s): Furuhashi H, Tomita K, Teratani T, Shimizu M, Nishikawa M, Higashiyama M, Takajo T, Shirakabe K, Maruta K, Okada Y, Kurihara C, Watanabe C, Komoto S, Aosasa S, Nagao S, Yamamoto J, Miura S, Hokari R.
  • Journal Title: Hepatol Res. Volume: 48 Issue: 5 Pages: 397-407
  • DOI: 10.1111/hepr.13040
• [Presentation] 新規NASH治療薬候補分子としての、Angiopoietin like protein-4の果たす役割に関する検討. (2020)
  • Author(s): 冨田謙吾, 東山正明, 穂苅量太
  • Organizer: 第24回日本肝臓学会大会
• [Presentation] 新規Wntリガンドである、Aortic carboxypeptidase-like proteinは、非アルコール性脂肪肝炎病態を増悪させる. (2018)
  • Author(s): 冨田謙吾、寺谷俊昭、金井隆典
  • Organizer: 第54回日本肝臓学会総会