Iron overload by iron metabolism dysregulation and UPR breakdown through the ER stress

• Project/Area Number: 25460969
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Ohtake Takaaki 旭川医科大学, 医学部, その他 (10359490)
• Co-Investigator(Kenkyū-buntansha): SASAKI Katsunori 旭川医科大学, 医学部, 特任教授 (60336394) ; TANAKA Hiroki 旭川医科大学, 医学部, 助教 (70596155)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 脂肪肝 / 鉄代謝異常 / 小胞体ストレス / UPR

Outline of Final Research Achievements

Non-alcoholic fatty liver disease frequently coexist iron overload. Iron dysregulation by hepcidin down-regulation is considered to be the cause as same as hereditary heamochromatosis. Bone morphogenetic protein binding endothelial regulator (BMPER) is inhibiting BMP-SMAD signaling by binding BMP extracellularly, subsequently reduces hepcidin transcription. Although BMPER was thought to be expressed by hepatocytes because of its vast protein expressing functions, it is noteworthy that we found out BMPER is expressed dominantly in liver sinusoid endothelial cells rather than hepatocytes.

Research Products

• [Journal Article] Heterogeneous nuclear ribonucleoprotein A1 improves the intestinal injury by regulating apoptosis via trefoil factor 2 in mice with anti-CD3-induced enteritis. (2015)
  • Author(s): Ando K, Fujiya M, Konishi H, Ueno N, Inaba Y, Moriichi K, Ikuta K, Tanabe H, Ohtake T, Kohgo Y.
  • Journal Title: Inflammatory Bowel Diseases Volume: 21 Issue: 7 Pages: 1541-1552
  • DOI: 10.1097/mib.0000000000000401
  • Peer Reviewed
• [Journal Article] Polyphosphate, an active molecule derived from probiotic Lactobacillus brevis, improves the fibrosis in murine colitis. (2015)
  • Author(s): Kashima S, Fujiya M, Konishi H, Ueno N, Inaba Y, Moriichi K, Tanabe H, Ikuta K, Ohtake T, Kohgo Y.
  • Journal Title: Transl Res. Volume: in press Issue: 2 Pages: 00069-9
  • DOI: 10.1016/j.trsl.2015.02.002
  • NAID: 120005837997
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic nerve growth factor induced by iron overload triggers defenestration in liver sinusoidal endothelial cells. (2015)
  • Author(s): Addo L, Tanaka H, Yamamoto M, Toki Y, Ito S, Ikuta K, Sasaki K, Ohtake T, Torimoto Y, Fujiya M, Kohgo Y.
  • Journal Title: Biochim Biophys Acta Volume: 1852(1) Issue: 1 Pages: 175-83
  • DOI: 10.1016/j.bbadis.2014.11.014
  • Peer Reviewed
• [Journal Article] Up-regulation of iron regulatory hormone hepcidin by interferon α. (2014)
  • Author(s): Ichiki K, Ikuta K, Addo L, Tanaka H, Sasaki Y, Shimonaka Y, Sasaki K, Ito S, Shindo M, Ohtake T, Fujiya M, Torimoto Y, Kohgo Y.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 29 Issue: 2 Pages: 387-394
  • DOI: 10.1111/jgh.12348
  • Peer Reviewed
• [Journal Article] Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of nonalcoholic fatty liver disease in mice. (2014)
  • Author(s): Sawada K, Ohtake T, Hasebe T, Abe M, Tanaka H, Ikuta K, Suzuki Y, Fujiya M, Hasebe C, Kohgo Y.
  • Journal Title: Hepatology Research Volume: in press Issue: 8 Pages: 920-34
  • DOI: 10.1111/hepr.12199
  • Peer Reviewed
• [Presentation] マウス脂肪肝鉄代謝異常における非実質細胞パラクライン作用に関する研究 (2015)
  • Author(s): 長谷部拓夢、澤田康司、中嶋駿介、大竹孝明、藤谷幹浩、高後裕
  • Organizer: JDDW 2015 第19回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] 肝非実質細胞産生のBMPERがマウス脂肪肝の鉄代謝異常を誘導する (2015)
  • Author(s): 長谷部拓夢、大竹孝明、高後裕
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-22
• [Presentation] NAFLD病態における腸内フローラ・脂質代謝・自然免疫の相互作用 (2015)
  • Author(s): 澤田康司、大竹孝明、高後裕
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] 高脂肪食負荷マウス脂肪肝の鉄代謝異常におけるBMP-Smadシグナル抑制メカニズムの関与 (2015)
  • Author(s): 長谷部拓夢、大竹孝明、高後裕
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] Fatty acids induce the expression of TLRs as the pro-inflammatory state in NAFLD mice liver. (2013)
  • Author(s): Sawada K, Ohtake T, Hasebe T, Nakajima S, Abe M, Tanaka H, Kohgo Y.
  • Organizer: The 64th Annual Meeting of American Association for the Study of Liver Diseases.
  • Place of Presentation: Washington, DC
• [Presentation] NAFLD病態におけるTLRシグナル異常と腸内フローラの意義．
  • Author(s): 澤田康司、前田重明、阿部真美、大竹孝明、高後裕．
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 鹿児島