Elucidation of pathogenesis of the onset of lifestyle-related diseases due to oxidative stress derived from diet components

• Project/Area Number: 25461372
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The Institute for Adult Diseases Asahi Life Foundation
• Principal Investigator: Kushiyama Akifumi 公益財団法人朝日生命成人病研究所, その他部局等, 教授 (30435820)
• Co-Investigator(Renkei-kenkyūsha): SAKODA Hideyuki 宮崎大学, 第三内科, 講師 (50376464) ; ASANO Tomoichirou 広島大学, 大学院医歯薬保健学研究院, 教授 (70242063) ; KURIHARA Hiroki 東京大学, 大学院医学研究科, 教授 (20221947)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 生活習慣病 / 尿酸 / キサンチンオキシダーゼ

Outline of Final Research Achievements

The diet components, especially sugar and lipid, are closely related to the development of lifestyle-related diseases. Although, the components are strongly influenced to the activity of Xanthine oxidoreductase, XOR, playing a role as rate-limiting enzyme of uric acid metabolism with accompanying ROS generation.
Our previous study clarified the involvement of macrophage-derived XOR activity in pathogenesis of atherosclerosis. In this study, I established the mice strains which change tissue-specific expression of XOR. They were fed with a various diets' load and their lifestyle-related diseases get worse. The analysis of these mice were partly clarified the involvement of the XOR activation due to the diet component.

Research Products

• [Journal Article] C-Peptide Level in Fasting Plasma and Pooled Urine Predicts HbA1c after Hospitalization in Patients with Type 2 Diabetes Mellitus. (2016)
  • Author(s): Sonoda R, Tanaka K, Kikuchi T, Onishi Y, Takao T, Tahara T, Yoshida Y, Suzawa N, Kawazu S, Iwamoto Y, Kushiyama A.
  • Journal Title: PLoS One. Volume: 11 Issue: 2 Pages: e0147303-e0147303
  • DOI: 10.1371/journal.pone.0147303
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. (2016)
  • Author(s): Okubo H, Kushiyama A, Sakoda H, Nakatsu Y, Iizuka M, Taki N, Fujishiro M, Fukushima T, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Asahara T, Yoshida Y, Chonan O, Encinas J, Asano T.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 20157-20157
  • DOI: 10.1038/srep20157
  • NAID: 120006796541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. (2015)
  • Author(s): Qiang S, Nakatsu Y, Seno Y, Fujishiro M, Sakoda H, Kushiyama A, Mori K, Matsunaga Y, Yamamotoya T, Kamata H, Asano T.
  • Journal Title: Diabetol Metab Syndr. Volume: 7 Issue: 1 Pages: 104-104
  • DOI: 10.1186/s13098-015-0102-8
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit (2015)
  • Author(s): Nakatsu Y, Iwashita M, Sakoda H, Ono H, Nagata K, Matsunaga Y, Fukushima T, Fujishiro M, Kushiyama A, Kamata H, Takahashi S, Katagiri H, Honda H, Kiyonari H, Uchida T, Asano T
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24255-24266
  • DOI: 10.1074/jbc.m115.658559
  • Peer Reviewed / Open Access
• [Journal Article] LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis. (2015)
  • Author(s): Matsunaga Y, Nakatsu Y, Fukushima T, Okubo H, Iwashita M, Sakoda H, Fujishiro M, Yamamotoya T, Kushiyama A, Takahashi S, Tsuchiya Y, Kamata H, Tokunaga F, Iwai K, Asano T.
  • Journal Title: Mediators Inflamm. Volume: 2015 Issue: 1 Pages: 125380-125380
  • DOI: 10.1155/2015/125380
  • Peer Reviewed / Open Access
• [Journal Article] High-fat diet feeding significantly attenuates anagliptin-induced regeneration of islets of Langerhans in streptozotocin-induced diabetic mice (2015)
  • Author(s): Ｓhinjo T, Nakatsu Y, Iwashita M, Sano T, Sakoda H, Ishihara H, Kushiyama A, Fujishiro M, Nishimura F, Asano T.
  • Journal Title: Diabetol Metab Syndr Volume: ７ Issue: 1 Pages: 50-50
  • DOI: 10.1186/s13098-015-0047-y
  • Peer Reviewed / Open Access
• [Journal Article] Protection from diet-induced obesity and insulin resistance in mice lacking CCL19-CCR7 signaling. (2015)
  • Author(s): Sano T, Iwashita M, Nagayasu S, Yamashita A, Shinjo T, Hashikata A, Asano T, Kushiyama A, Ishimaru N, Takahama Y, Nishimura F
  • Journal Title: Obesity Volume: 23 Issue: 7 Pages: 1460-1471
  • DOI: 10.1002/oby.21127
  • Peer Reviewed / Open Access
• [Journal Article] Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines. (2015)
  • Author(s): Kanaoka R, Kushiyama A, Seno Y, Nakatsu Y, Matsunaga Y, Fukushima T, Tsuchiya Y, Sakoda H, Fujishiro M, Yamamotoya T, Kamata H, Matsubara A, Asano T.
  • Journal Title: PLoS One. Volume: 10 (6) Issue: 6 Pages: e0127467-e0127467
  • DOI: 10.1371/journal.pone.0127467
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation. (2015)
  • Author(s): Shinjo T, Nakatsu Y, Iwashita M, Sano T, Sakoda H, Ishihara H, Kushiyama A, Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H, Nishimura F, Asano T.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 309(3) Issue: 3 Pages: E214-E223
  • DOI: 10.1152/ajpendo.00553.2014
  • Peer Reviewed
• [Journal Article] The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. (2015)
  • Author(s): Nakatsu Y, Seno Y, Kushiyama A, Sakoda H, Fujishiro M, Katasako A, Mori K, Matsunaga Y, Fukushima T, Kanaoka R, Yamamotoya T, Kamata H, Asano T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 309(1) Issue: 1 Pages: G42-G51
  • DOI: 10.1152/ajpgi.00443.2014
  • Peer Reviewed
• [Journal Article] Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model. (2015)
  • Author(s): Hirofumi Okubo, Yusuke Nakatsu, Hideyuki Sakoda, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yasuka Matsunaga, Haruya Ohno, Masayasu Yoneda, Hideaki Kamata, Takanori Shinjo, Misaki Iwashita, Fusanori Nishimura, and Tomoichiro Asano
  • Journal Title: Am. J. Physiol. Gastrointest. Liver Physiol. Volume: 308 Issue: 2 Pages: 151-158
  • DOI: 10.1152/ajpgi.00198.2014
  • Peer Reviewed
• [Journal Article] Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes (2014)
  • Author(s): Kentaro Tanaka, Shigeko Hara, Masakazu Hattori, Ken Sakai, Yukiko Onishi, Yoko Yoshida, Shoji Kawazu
  • Journal Title: Journal of Diabetes Investigation Volume: - Issue: 1 Pages: 98-104
  • DOI: 10.1111/jdi.12243
  • Peer Reviewed / Open Access
• [Journal Article] Linking uric acid metabolism to diabetic complications. (2014)
  • Author(s): Kushiyama A, Tanaka K, Hara S, Kawazu S.
  • Journal Title: World J Diabetes Volume: 15 Issue: 6 Pages: 787-795
  • DOI: 10.4239/wjd.v5.i6.787
  • Peer Reviewed / Open Access
• [Journal Article] he Inflammation-lipocalin2 axis may contribute to the development of chronic kidney disease. (2014)
  • Author(s): Hashikata A, Yamashita A, Suzuki S, Nagayasu S, Shinjo T, Taniguchi A, Fukushima M, Nakai Y, Nin K, Watanabe N, Asano T, Abiko Y, Kushiyama A, Nagasaka S, Nishimura F.
  • Journal Title: Nephrol Dial Transplant Volume: ２９ Issue: 3 Pages: 611-618
  • DOI: 10.1093/ndt/gft449
  • Peer Reviewed / Open Access
• [Journal Article] 尿酸代謝と生活習慣病の新知見 (2014)
  • Author(s): 櫛山 暁史
  • Journal Title: 生体の科学 Volume: 65 Pages: 11-11
• [Journal Article] Twenty-year trend of increasing obesity in young patients with poorly controlled type 2 diabetes at first diagnosis in urban Japan. (2013)
  • Author(s): Kushiyama A, Yoshida Y, Kikuchi T, Suzawa N, Yamamoto M, Tanaka K, Okayasu M, Tahara T, Takao T, Onishi Y, Kawazu S.
  • Journal Title: Journal of Diabetes Investigation Volume: 4 Issue: 6 Pages: 540-545
  • DOI: 10.1111/jdi.12090
  • Peer Reviewed
• [Journal Article] Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development. (2013)
  • Author(s): Kushiyama A, Sakoda H, Oue N, Okubo M, Nakatsu Y, Ono H, Fukushima T, Kamata H, Nishimura F, Kikuchi T, Fujishiro M, Nishiyama K, Aburatani H, Kushiyama S, Iizuka M, Taki N, Encinas J, Sentani K, Ogonuki N, Ogura A, Kawazu S, Yasui W, Higashi Y, Kurihara H, Katagiri H, Asano T.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 33 Issue: 8 Pages: 1986-1993
  • DOI: 10.1161/atvbaha.113.301546
  • Peer Reviewed / Open Access
• [Journal Article] Lactobacillus casei strain Shirota protects against non-alcoholic steatohepatitis development in a rodent model (2013)
  • Author(s): Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, Matsunaga Y, Kamata H, Asahara T, Yoshida Y, Chonan O, Iwashita M, Nishimura F, Asano T
  • Journal Title: American Journal Physiolgy-Gastrointestinal and Liver Physiogy Volume: 305 Issue: 12 Pages: 911-918
  • DOI: 10.1152/ajpgi.00225.2013
  • Peer Reviewed
• [Journal Article] Par14 associates with IRS-1, thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions. (2013)
  • Author(s): Zhang J, Nakatsu Y, Sinjo T, Guo Y, Sakoda H, Yamamotoya T, Otani Y, Okubo H, Kushiyama A, Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H, Nishimura F, Katagiri H, Takahashi SI, Kurihara H, Uchida T, Asano T.
  • Journal Title: Ｊournal of Biological Chemistry Volume: 288 Issue: 28 Pages: 20692-20701
  • DOI: 10.1074/jbc.m113.485730
  • Peer Reviewed
• [Presentation] Novel insights into anti-diabetic effects of sex hormone binding globulin (SHBG): anti-inflammatory actions on both adipocytes and macrophages (2015)
  • Author(s): H Yamazaki, A Kushiyama, H Sakoda, M Fujishiro, T Asano
  • Organizer: Diabetes: New Insights into Molecular Mechanisms and Therapeutic Strategies Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: 京都府
  • Year and Date: 2015-10-25
• [Presentation] Extrahepatic xanthine oxidoreductase as a therapeutic target for diabetes mellitus and its complications (2015)
  • Author(s): A Kushiyama, T Kikuchi, H Yamazaki, H Sakoda, Y Iwamoto, T Asano
  • Organizer: Diabetes: New Insights into Molecular Mechanisms and Therapeutic Strategies Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: 京都府
  • Year and Date: 2015-10-25
• [Presentation] フルクトースの誘導する炎症におけるマクロファージ由来キサンチン酸化還元酵素の役割 (2015)
  • Author(s): 櫛山 暁史
  • Organizer: 第6回Molecular Cardiovascular Conference II
  • Place of Presentation: 兵庫県
  • Year and Date: 2015-09-04
• [Presentation] 尿酸代謝と粥状動脈硬化 ・高すぎる尿酸値と低すぎる尿酸値の動脈硬化リスク (2015)
  • Author(s): 櫛山 暁史
  • Organizer: 第47回 動脈硬化学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2015-07-09
• [Presentation] マクロファージにおける糖代謝による活性酸素産生とインスリン抵抗性 (2015)
  • Author(s): 櫛山暁史、菊池貴子、迫田秀之、藤城緑、山崎広貴、山本屋武、大久保博史、中津祐介、河津捷二、岩本安彦、浅野知一郎
  • Organizer: 第58回日本糖尿病学会学術集会
  • Place of Presentation: 山口県
  • Year and Date: 2015-05-21
• [Presentation] 糖代謝に伴う核酸代謝由来酸化ストレスと臓器障害 (2014)
  • Author(s): 櫛山 暁史、櫛山 櫻、菊池 貴子、栗原 裕基、浅野 知一郎、河津 捷二
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] resistin like moleculeβを介した マクロファージ分化と炎症 (2014)
  • Author(s): 櫛山暁史 菊池貴子、迫田秀之、藤城緑、山崎広貴、山本屋武、大久保博史、中津祐介、河津捷二、浅野知一郎
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] 食事成分に起因する組織特異的キサンチン酸化還元酵素を介した核酸代謝と酸化ストレス (2014)
  • Author(s): 櫛山暁史、菊池貴子、藤田政子、櫛山櫻、浅野知一郎、西山功一、栗原裕基
  • Organizer: 第5回MCC（Molecular Cardiovascular Conference） II
  • Place of Presentation: 大阪
  • Year and Date: 2014-09-04 – 2014-09-05
• [Presentation] Involvement of Resistin-like molecule β in the development of non-alcoholic steatohepatitis (2014)
  • Author(s): Akifumi Kushiyama, Hirofumi Okubo, Yusuke Nakatsu, Hideyuki Sakoda, Midori Fujishiro, Toshiaki Fukushima, Shin-ichiro Takahashi, Tomoichiro Asano
  • Organizer: 第74回米国糖尿病学会議
  • Place of Presentation: 米国サンフランシスコ
  • Year and Date: 2014-06-13 – 2014-06-17
• [Presentation] マクロファージresistin like moleculeβによるインスリン抵抗性・動脈硬化発症の機序 (2014)
  • Author(s): 櫛山暁史 菊池貴子、迫田秀之、藤城緑、山崎広貴、山本屋武、大久保博史、中津祐介、河津捷二、浅野知一郎
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] キサンチンオキシダーゼ阻害剤FebuxostatによるNASH改善作用の検討 (2014)
  • Author(s): 藤城緑、中津祐介、福嶋俊明、松永泰花、迫田秀之、櫛山暁史、山本屋武、西村英紀、浅野知一郎
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Macrophage resistin-like molecule β is involved in atherosclerosis development. (2014)
  • Author(s): Akifumi Kushiyama, Takako Kikuchi, Hideyuki Sakoda, Koichi Nishiyama, Hiroki Kurihara, Tomoichiro Asano, Shoji Kawazu
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] 空腹時活性化GLP-1によるDPP4阻害薬シタグリプチンの効果予測 (2013)
  • Author(s): 櫛山暁史，菊池貴子，大西由希子，田原たづ，髙尾淑子，山本万友美，須澤直木，吉田洋子，河津捷二
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本県
• [Presentation] Involvement of macrophage-derived resistin like molecule β in atherosclerosis development (2013)
  • Author(s): A. Kushiyama, T. Kikuchi, H. Sakoda, M. Fujishiro, K. Nishiyama, H. Kurihara, Y. Higashi, S. Kawazu, T. Asano
  • Organizer: 第45回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京都
• [Presentation] 食事成分が誘引となる血管障害 (2013)
  • Author(s): 櫛山暁史，菊池貴子，櫛山 櫻，浅野知一郎，西山功一，栗原裕基
  • Organizer: 第4回 Molecular Cardiovascular Conference II
  • Place of Presentation: 北海道
• [Presentation] Multifunctional Cardiography（MCG）を用いた2型糖尿病患者の心筋虚血の検出 (2013)
  • Author(s): 常田智子，福井美弥子，新井 恵，難波敏子，宮城よう子，吉川美帆，山本美津代，板橋 明，田原たづ，吉田洋子，河津捷二，櫛山暁史
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本県
• [Book] 『ここまで明らかになった！尿酸代謝ワールドと高尿酸血症の病態解明～診療と医学の最前線～』(動脈硬化（尿酸と血管リモデリング）の形成と進展 アテローム性動脈硬化) (2015)
  • Author(s): 櫛山暁史
  • Publisher: メディカルレビュー社
• [Book] 生体の科学 (2014)
  • Author(s): 櫛山暁史
  • Publisher: 金原一郎医学医療振興財団
• [Remarks] 朝日生命成人病研究所 研究所部門
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• [Remarks] 研究部 糖尿病代謝科 糖代謝生理学研究班
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