Establishment of novel therapies for steatohepatitis and liver cancer, by targeting the free cholesterol-mediated signaling pathway.

• Project/Area Number: 15K09031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• 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)
• Co-Investigator(Renkei-kenkyūsha): SHIMIZU Takahiko 千葉大学, 医学部, 客員准教授 (40301791)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 非アルコール性脂肪肝炎 / 遊離コレステロール / TLR9 / アセトアミノフェン肝障害 / 類洞内皮細胞 / 肝臓癌 / コレステロール / 細胞老化

Outline of Final Research Achievements

The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs.

Research Products

• [Journal Article] Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling (2017)
  • Author(s): Teratani Toshiaki、Tomita Kengo、Suzuki Takahiro、Furuhashi Hirotaka、Irie Rie、Hida Shigeaki、Okada Yoshikiyo、Kurihara Chie、Ebinuma Hirotoshi、Nakamoto Nobuhiro、Saito Hidetsugu、Hibi Toshifumi、Miura Soichiro、Hokari Ryota、Kanai Takanori
  • Journal Title: Journal of Hepatology Volume: 67 Issue: 4 Pages: 780-790
  • DOI: 10.1016/j.jhep.2017.05.020
  • Peer Reviewed / Open Access
• [Journal Article] Uric acid ameliorated indomethacin-induced enteropathy in mice through its antioxidant activity. (2017)
  • Author(s): Yasutake Y, Tomita K, Higashiyama M, Furuhashi H, Shirakabe K, Takajo T, Maruta K, Sato H, Narimatsu K, Yoshikawa K, Okada Y, Kurihara C, Watanabe C, Komoto S, Nagao S, Matsuo H, Miura S, Hokari R.
  • Journal Title: J Gastroenterol Hepatol. Volume: 印刷中 Issue: 11 Pages: 1839-1845
  • DOI: 10.1111/jgh.13785
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorcitoid receptor signaling. (2017)
  • Author(s): Yoshikawa K, Kurihara C, Furuhashi H, Takajo T, Maruta K, Yasutake Y, Sato H, Narimatsu K, Okada Y, Higashiyama M, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Tajiri H, Hokari R.
  • Journal Title: J Gastroenterol. Volume: 52 Issue: 1 Pages: 61-71
  • DOI: 10.1007/s00535-016-1205-1
  • Peer Reviewed
• [Journal Article] Platelet interaction with lyphatics aggravates intestinal inflammation by suppressing lymphangiogenesis. (2016)
  • Author(s): Sato H, Higashiyama M, Hozumi H, Sato S, Furuhashi H, Takajo T, Maruta K, Yasutake Y, Narimatsu K, Yoshikawa K, Kurihara C, Okada Y, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Hokari R.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 311 Issue: 2 Pages: G276-G285
  • DOI: 10.1152/ajpgi.00455.2015
  • Peer Reviewed
• [Journal Article] Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease. (2016)
  • Author(s): Jun Morinaga, Tsuyoshi Kadomatsu, Keishi Miyata, Motoyoshi Endo, Kazutoyo Terada, Zhe Tian, Taichi Sugizaki, Hiroki Tanigawa, Jiabin Zhao, Shunshun Zhu, Michio Sato, Kimi Araki, Ken-ichi Iyama, Kengo Tomita, Masashi Mukoyama, Kimio Tomita, Kenichiro Kitamura, Yuichi Oike
  • Journal Title: Kidney International Volume: 89 Issue: 2 Pages: 327-341
  • DOI: 10.1016/j.kint.2015.12.021
  • Peer Reviewed
• [Journal Article] Endoscopic and clinical evaluation of treatment and prognosis of Cronkhite-Canada syndrome: a Japanese nationwide survey. (2016)
  • Author(s): Watanabe C, Komoto S, Tomita K, Hokari R, Tanaka M, Hirata I, Hibi T, Kaunitz JD, Miura S
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 4 Pages: 327-336
  • DOI: 10.1007/s00535-015-1107-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recombinant Thrombomodulin Modulates Murine Colitis Possibly via High-Mobility Group Box 1 Protein Inhibition. (2015)
  • Author(s): Ueda T, Higashiyama M, Narimatsu K, Yasutake Y, Kurihara C, Okada Y, Watanabe C, Yoshikawa K, Maruta K, Komoto S, Tomita K, Nagao S, Hokari R, Miura S
  • Journal Title: Digestion Volume: 92 Pages: 108-119
  • Peer Reviewed
• [Journal Article] Randomized study comparing vitamin D3 and 1α-Hydroxyvitamin D3 in combination with pegylated interferon/ribavirin therapy for chronic hepatitis C. (2015)
  • Author(s): Omori-Mizuno Y, Nakayama N, Inao M, Funyu J, Asabe S, Tomita K, Nishikawa K, Hosoda Y, Tanaka M, Hashimoto Y, Yakabi K, Koshima Y, Mochida S
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 30 Issue: 9 Pages: 1384-1390
  • DOI: 10.1111/jgh.12949
  • Peer Reviewed
• [Journal Article] Lethal hemorrhage from duodenal ulcer due to small pancreatic cancer. (2015)
  • Author(s): Higashiyama M, Suzuki H, Watanabe C, Tomita K, Komoto S, Nagao S, Nakanishi K, Miura S, Hokari R
  • Journal Title: Clinical Journal of Gastroenterology Volume: 8 Issue: 4 Pages: 236-239
  • DOI: 10.1007/s12328-015-0586-7
  • Peer Reviewed
• [Journal Article] Beneficial effect of an omega-6 PUFA-rich diet in non-steroidal anti-inflammatory drug-induced mucosal damage in the murine small intestine. (2015)
  • Author(s): Ueda T, Hokari R, Higashiyama M, Yasutake Y, Maruta K, Kurihara C, Tomita K, Komoto S, Okada Y, Watanabe C, Usui S, Nagao S, Miura S
  • Journal Title: World Journal of Gastroenterology Volume: 21 Issue: 1 Pages: 177-186
  • DOI: 10.3748/wjg.v21.i1.177
  • Peer Reviewed
• [Journal Article] Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling. (2015)
  • Author(s): Narimatsu K, Higashiyama M, Kurihara C, Takajo T, Maruta K, Yasutake Y, Sato H, Okada Y, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Hokari R
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 30 Issue: 11 Pages: 1610-1617
  • DOI: 10.1111/jgh.12980
  • Peer Reviewed
• [Journal Article] No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis (2015)
  • Author(s): Kagawa T, Hirose S, Arase Y, Oka A, Anzai K, Tsuruya K, Shiraishi K, Orii R, Ieda S, Nakazawa T, Tomita K, Hokari R, Miura S, Ebinuma H, Saito H, Kitamura T, Horie Y, Okuse C, Wasada M, Inoko H, Tohkin M, Saito Y, Maekawa K, Takikawa H, Mine T
  • Journal Title: Drug Metabolism and Disposition Volume: 43 Issue: 5 Pages: 691
  • DOI: 10.1124/dmd.114.061325
  • Peer Reviewed
• [Journal Article] Pregnant woman with non-comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: A case report. (2015)
  • Author(s): Sato H, Tomita K, Yasue C, Umeda R, Ebinuma H, Ogata S, Du W, Soga S, Maruta K, Yasutake Y, Narimatsu K, Usui S, Watanabe C, Komoto S, Teratani T, Suzuki T, Yokoyama H, Saito H, Nagao S, Hibi T, Miura S, Kanai T, Hokari R.
  • Journal Title: Hepatology Research Volume: 45 Issue: 3 Pages: 349-355
  • DOI: 10.1111/hepr.12344
  • Peer Reviewed
• [Journal Article] Magnetic resonance enterocolonography in detecting erosion and redness in intestinal mucosa of patients with Crohn's disease. (2015)
  • Author(s): Sato H, Tamura C, Narimatsu K, Shimizu M, Takajyo T, Yamashita M, Inoue Y, Ozaki H, Furuhashi H, Maruta K, Yasutake Y, Yoshikawa K, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Shinmoto H, Hokari R
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 30 Issue: 4 Pages: 667-673
  • DOI: 10.1111/jgh.12851
  • Peer Reviewed
• [Presentation] ASH/NASH新規治療標的としての、肝星細胞遊離コレステロール制御機構の解析 (2015)
  • Author(s): 冨田謙吾、穂苅量太、金井隆典
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本県熊本市
  • Year and Date: 2015-05-21