The role of central-mediated hepatic responses in the obesity-induced impediment of hepatic regeneration

• Project/Area Number: 26670599
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kanazawa University
• Principal Investigator: Inoue Hiroshi 金沢大学, 新学術創成研究機構, 教授 (50397832)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 外科 / 肝切除 / 脂肪肝

Outline of Final Research Achievements

Brain-mediated hepatic responses, including gluconeogenic suppression, are mediated by the vagus nerve and hepatic IL-6/STAT3 activation. Meanwhile, hepatic STAT3 is known as the master regulator of hepatic regeneration, controlling the expressions of anti-apoptotic genes and cell-cycle related genes. In this project, we elucidate the mechanism of how brain regulates the vagus nerve and hepatic STAT3 activation. Further, we have found that the central-mediated hepatic responses are impeded in obesity. While hepatic regeneration is impaired in insulin-resistance and obesity, the impeded brain-mediated hepatic responses may be related to the obesity-induced dysfunction of hepatic regeneration.

Research Products

• [Journal Article] Centra insulin-action activates Kupffer cells by suppressing hepatic vagal activation through nicotinic alpha 7 acetylcholine receptor. (2016)
  • Author(s): Kimura K, Tanida M, Nagata N, Inaba Y, Watanabe H, Nagashimada M, Ota T, Asahara S, Kido Y, Matsumoto M, Toshinai K, Nakazato M, Shibamoto T, Kaneko S, Kasuga M, Inoue H
  • Journal Title: Cell reports Volume: 14 Issue: 10 Pages: 2362-2374
  • DOI: 10.1016/j.celrep.2016.02.032
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocyte β-Klotho regulates lipid homeostasis but not body weight in mice. (2016)
  • Author(s): Kobayashi K, Tanaka T, Okada S, Morimoto Y, Matsumura S, Manio MC, Inoue K, Kimura K, Yagi T, Saito Y, Fushiki T, Inoue H, Matsumoto M, Nabeshima Y.
  • Journal Title: FASEB J. Volume: 30 Issue: 2 Pages: 849-62
  • DOI: 10.1096/fj.15-274449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β cell mass via epigenetic modification of Cdkn1c. (2015)
  • Author(s): Asahara S, Etoh H, Inoue H, Teruyama K, Shibutani Y, Ihara Y, Kawada Y, Bartolome A, Hashimoto N, Matsuda T, Koyanagi-Kimura M, Kanno A, Hirota Y, Hosooka T, Nagashima K, Nishimura W, Inoue H, Matsumoto M, Higgins MJ, Yasuda K, Inagaki N, Seino S, Kasuga M, Kido Y.
  • Journal Title: Proceedings of the National Acaddemy of Scienceof the United States of America Volume: 112(27) Issue: 27 Pages: 8332-8337
  • DOI: 10.1073/pnas.1422104112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gadd34 regulates liver regeneration in hepatic steatosis. (2015)
  • Author(s): Inaba Y, Furutani T, Kimura K, Watanabe H, Haga S, Kido Y, Yamamoto Y, Harada K, Kaneko S, Oyadomari S, Ozaki M, Kasuga M, Inoue H.
  • Journal Title: Hepatology Volume: 61(4) Issue: 4 Pages: 1343-1356
  • DOI: 10.1002/hep.27619
  • Peer Reviewed / Open Access
• [Journal Article] Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice. (2015)
  • Author(s): Tsuneki H, Tokai E, Nakamura Y, Takahashi K, Fujita M, Asaoka T, Kon K, Anzawa Y, Wada T, Takasaki I, Kimura K, Inoue H, Yanagisawa M, Sakurai T, Sasaoka T.
  • Journal Title: Diabetes Volume: 64 Issue: 2 Pages: 459-470
  • DOI: 10.2337/db14-0695
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular basis of brain-mediated regulation of hepatic glucose metabolism. (2014)
  • Author(s): Inoue H.
  • Journal Title: Diabetol Int. Volume: 5 Issue: 3 Pages: 158-164
  • DOI: 10.1007/s13340-014-0185-8
  • NAID: 40020204115
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model. (2014)
  • Author(s): Haga S, Ozawa T, Yamada Y, Morita N, Nagashima I, Inoue H, Inaba Y, Noda N, Abe R, Umezawa K, Ozaki M.
  • Journal Title: Antioxid Redox Signal. Volume: 21 Issue: 18 Pages: 2515-2530
  • DOI: 10.1089/ars.2013.5391
  • NAID: 120005677747
  • Peer Reviewed
• [Journal Article] Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. (2014)
  • Author(s): Tanaka M, Ikeda K, Suganami T, et al.
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4982-4982
  • DOI: 10.1038/ncomms5982
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis. (2014)
  • Author(s): Harada K, Kakuda Y, Sato Y, Ikeda H, Shimoda S, Yamamoto Y, Inoue H, Ohta H, Kasashima S, Kawashima A, Nakanuma Y.
  • Journal Title: J Clin Pathol Volume: 67(5) Issue: 5 Pages: 396-402
  • DOI: 10.1136/jclinpath-2013-201815
  • NAID: 120005469783
  • Peer Reviewed / Open Access
• [Presentation] 視床下部を介した栄養素による肝糖代謝調節 (2015)
  • Author(s): 井上啓
  • Organizer: 第38回日本分子生物学会 第88回日本生化学会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-02
• [Presentation] 迷走神経による肝糖産生制御 (2015)
  • Author(s): 井上啓
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-23
• [Presentation] 中枢神経インスリン作用による肝糖代謝調節メカニズムの解明 (2015)
  • Author(s): 井上啓
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-25
• [Presentation] NALFDに伴う肝再生障害におけるGadd34の役割の解明 (2014)
  • Author(s): 稲葉有香、尾崎倫孝、親泊政一、春日雅人、井上啓
  • Organizer: 第26回分子糖尿病学シンポジウム
  • Place of Presentation: 高知市文化プラザ
  • Year and Date: 2014-12-06
• [Presentation] Gadd34は脂肪肝での肝再生障害を改善する (2014)
  • Author(s): 稲葉有香、松本道宏、春日雅人、井上啓
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎シーガイアコンベンションセンター
  • Year and Date: 2014-10-25
• [Remarks] 金沢大学新学術創成研究機構井上研究室ホームページ
  • URL: http://inoue.w3.kanazawa-u.ac.jp/index.html
• [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井上研究室業績一覧
  • URL: http://inoue.w3.kanazawa-u.ac.jp/index.html
• [Patent(Industrial Property Rights)] 肝臓脂肪蓄積抑制剤 (2015)
  • Inventor(s): 井上啓
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-04-23