Development of novel pharmacological treatments for nonalcoholic steatohepatitis: an application of carotenoid compound

• Project/Area Number: 25282017
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Kanazawa University
• Principal Investigator: Ota Tsuguhito 金沢大学, 脳・肝インターフェースメディシン研究センター, 准教授 (60397213)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2014: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: β-クリプトキサンチン / アスタキサンチン / インスリン抵抗性 / 脂肪肝 / NASH / マクロファージ / カロテノイド / 炎症 / 糖尿病 / 肥満

Outline of Final Research Achievements

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this study, we　found the novel molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. We propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, can be as a novel nutraceutical and be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.

Research Products

• [Journal Article] Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E (2015)
  • Author(s): Ni Y, Nagashimada M, Zhuge F, Zhan L, Nagata N, Tsutsui A, Nakanuma Y, Kaneko S, Ota T
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 17192-17192
  • DOI: 10.1038/srep17192
  • NAID: 120005682635
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prevention and reversal of lipotoxicity-induced hepatic insulin resistance and steatohepatitis in mice by an antioxidant carotenoid, beta-cryptoxanthin (2015)
  • Author(s): Ni Y, Nagashimada M, Zhan. L, Nagata N, Kobori M, Sugiura M, Ogawa K, Kaneko S, Ota T.
  • Journal Title: Endocrinology Volume: 156 Issue: 3 Pages: 987-999
  • DOI: 10.1210/en.2014-1776
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Roles of chemokines and chemokine receptors in obesity-associated insulin resistance and nonalcoholic fatty liver disease. (2015)
  • Author(s): Xu L, Kitade H, Ni Y, Ota T
  • Journal Title: Biomolecules Volume: 5 Issue: 3 Pages: 1563-1579
  • DOI: 10.3390/biom5031563
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Obesity-induced inflammation and insulin resistance (2014)
  • Author(s): Ota T
  • Journal Title: Front Endocrinol Volume: 5 Pages: 204-204
  • DOI: 10.3389/fendo.2014.00204
  • Peer Reviewed
• [Journal Article] β-Cryptoxanthin alleviates diet-induced nonalcoholic steatohepatitis by suppressing inflammatory gene expression in mice (2014)
  • Author(s): Kobori M, Ni Y, Takahashi Y, Watanabe N, Sugiura M, Ogawa K, Nagashimada M, Kaneko S, Naito S, Ota, T
  • Journal Title: PLoS One Volume: 9 Issue: 5 Pages: e98294-e98294
  • DOI: 10.1371/journal.pone.0098294
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. (2014)
  • Author(s): Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T
  • Journal Title: Diabetologia Volume: 57 Issue: 9 Pages: 1968-1976
  • DOI: 10.1007/s00125-014-3306-9
  • NAID: 120005463349
  • Peer Reviewed / Open Access
• [Journal Article] Ectopic fat accumulation and distant organ-specific insulin resistance in Japanese people with nonalcoholic Fatty liver disease (2014)
  • Author(s): K Kato, T Takamura, Y Takeshita, Y Ryu, H Misu, T Ota, K Tokuyama, S Nagasaka, M Matsuhisa, O Matsui, S Kaneko
  • Journal Title: PLoS One Volume: 9(3) Issue: 3 Pages: e92170-e92170
  • DOI: 10.1371/journal.pone.0092170
  • NAID: 120005440398
  • Peer Reviewed / Open Access
• [Journal Article] The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism : a randomised controlled trial (2014)
  • Author(s): Y Takeshita, T Takamura, M Honda, Y Kita, Y Zen, KI Kato, H Misu, T Ota, M Nakamura, K Yamada, H Sunagozaka, K Arai, T Yamashita, E Mizukoshi, S Kaneko
  • Journal Title: Diabetologia Volume: 57(5) Issue: 5 Pages: 878-90
  • DOI: 10.1007/s00125-013-3149-9
  • Peer Reviewed / Open Access
• [Journal Article] LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance (2014)
  • Author(s): Fei Lan, H Misu, K Chikamoto, H Takayam, A Kikuchi, K Mohri, N Takata, H Hayashi, N Matsuzawa-Nagata, Y Takeshita, H Noda, Y Matsumoto, T Ota, T Nagano, M Nakagen, K Miyamoto, K Takatsuki, T Seo, K Iwayama, K Tokuyama, S Matsugo, H Tang, Y Saito, S Yamagoe, S Kaneko, T Takamura
  • Journal Title: Diabete Volume: 63 Issue: 5 Pages: 1649-1664
  • DOI: 10.2337/db13-0728
  • Peer Reviewed / Open Access
• [Journal Article] Chemokine systems link obesity to insulin resistance. (2013)
  • Author(s): Ota T
  • Journal Title: Diabetes Metab J Volume: 37 Issue: 3 Pages: 165-172
  • DOI: 10.4093/dmj.2013.37.3.165
  • Peer Reviewed
• [Journal Article] Histidine augments the suppression of hepatic glucose production by central insulin action. (2013)
  • Author(s): Kimura K, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara S, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H.
  • Journal Title: Diabetes Volume: 62 Issue: 7 Pages: 2266-77
  • DOI: 10.2337/db12-1701
  • Peer Reviewed
• [Journal Article] CCR5: a novel player in the adipose tissue inflammation and insulin resistance? (2013)
  • Author(s): Ota T
  • Journal Title: Adipocyte Volume: 2 Issue: 2 Pages: 99-103
  • DOI: 10.4161/adip.22420
  • NAID: 40020812627
  • Peer Reviewed
• [Journal Article] Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver (2013)
  • Author(s): T Otoda, T Takamura, H Misu, T Ota, S Murata, H Hayashi, H Takayama, A Kikuchi, T Kanamori, KR Shima, F Lan, T Takeda, S Kurita, K Ishikura, Y Kita, K Iwayama, KI Kato, M Uno, Y Takeshita, M Yamamoto, K Tokuyama, S Iseki, K Tanaka, S Kaneko
  • Journal Title: Diabetes Volume: 62(3) Issue: 3 Pages: 811-24
  • DOI: 10.2337/db11-1652
  • Peer Reviewed
• [Presentation] NASH: Emerging Roles of Lipotoxicity and Astaxanthin (2015)
  • Author(s): Tsuguhito Ota
  • Organizer: 第104回中華民国（台湾）消化器系総合学術年会総会
  • Place of Presentation: 国立台大病院国際会議センター、台北、台湾
  • Year and Date: 2015-03-28 – 2015-03-29
  • Invited
• [Presentation] Astaxathin and lipotoxicity-induced NASH、The 13th Japan-Korea Diabetic Nephropathy Seminar (2014)
  • Author(s): Tsuguhito Ota
  • Organizer: The 13th Japan-Korea Diabetic Nephropathy Seminar
  • Place of Presentation: ニューグランドホテル、金沢、石川県
  • Year and Date: 2014-09-26
  • Invited
• [Presentation] 肝臓リポトキシシティへのアスタキサンチンの作用 (2014)
  • Author(s): 太田嗣人
  • Organizer: 第10回アスタキサンチンシンポジウム
  • Place of Presentation: 北海道大学医学部学友会館フラテ、札幌、北海道
  • Year and Date: 2014-09-12
  • Invited
• [Presentation] Common DiseaseとしてのNAFLD/NASHの臨床 (2014)
  • Author(s): 太田嗣人
  • Organizer: 日本内科学会第64回北陸支部生涯教育講演会
  • Place of Presentation: アイザック小杉文化ホールラポール、射水市、富山
  • Year and Date: 2014-09-07
  • Invited
• [Presentation] カロテノイドによる自然免疫への作用と脂肪肝炎の進展抑止 (2014)
  • Author(s): 太田嗣人
  • Organizer: 平成26年度カロテノイド若手の会
  • Place of Presentation: 石川県立大学、白山市、石川県
  • Year and Date: 2014-09-03
  • Invited
• [Presentation] The Chemokine System in Obesity-induced Insulin Resistance: a Possible Theraperutic Target? (2014)
  • Author(s): Tsuguhito Ota
  • Organizer: The 47th Spring Conference of the Korean Society of Lipidology & Atherosclerosis
  • Place of Presentation: Kimdaejung Convention Center、光州、韓国
  • Year and Date: 2014-04-18 – 2014-04-19
  • Invited
• [Presentation] Astaxathin and lipotoxicity-induced NASH (2014)
  • Author(s): 太田嗣人
  • Organizer: 第17回国際フリーラジカル会議 SFRRI2014
  • Place of Presentation: 京都国際会議場、京都
  • Invited
• [Presentation] Preventive Effect of Astaxanthin on Lipotoxic Model of NASH (2013)
  • Author(s): 太田嗣人
  • Organizer: 8th Asia Pacific Conference on Clinical Nutrition APCCN 2013
  • Place of Presentation: The Tokyo Bay Maihama Hotel Club、千葉
  • Invited
• [Presentation] Inhibitory effect of astaxanthin on the progression of lipotoxic model of nonalcoholic steatohepatitis (2013)
  • Author(s): 太田嗣人
  • Organizer: 第45回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル、東京
  • Invited
• [Presentation] カロテノイドによる脂肪肝炎の進展抑止
  • Author(s): 太田嗣人
  • Organizer: 日本薬学会関東支部第38回学術講演会
  • Place of Presentation: 日本薬学会長井記念館長井記念ホール、東京
  • Invited
• [Book] 脂肪肝の治療標的としての小胞体ストレス、別冊医学のあゆみレドックスUPDATE (2015)
  • Author(s): 太田嗣人
  • Total Pages: 5
  • Publisher: 医歯薬出版
• [Book] 糖尿病研修ノート改訂第２版 (2014)
  • Author(s): 太田嗣人
  • Total Pages: 5
  • Publisher: 診断と治療社
• [Book] 内分泌・糖尿病・代謝内科 (2014)
  • Author(s): 太田嗣人
  • Total Pages: 8
  • Publisher: 科学評論社
• [Book] Annual Review 糖尿病・代謝・内分泌2014 (2014)
  • Author(s): 太田嗣人
  • Total Pages: 213
  • Publisher: 中外医学社
• [Book] 糖尿病の分子標的と治療薬事典 (2013)
  • Author(s): 太田嗣人
  • Total Pages: 343
  • Publisher: 羊土社
• [Remarks] 金沢大学脳・肝インターフェースメディシン研究センター 太田研究室
  • URL: http://ota.w3.kanazawa-u.ac.jp/