The clarification of pathophysiological mechanism for over-nutritional fatty liver and the involvement of DNA damage by oxygen radical

• Project/Area Number: 23500846
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Oita University
• Principal Investigator: KAKUMA Tetsuya 大分大学, 医学部, 講師 (80343359)
• Co-Investigator(Kenkyū-buntansha): SEIKE Masataka 大分大学, 医学部, 助教 (40253794) ; MASAKI Takayuki 大分大学, 医学部, 助教 (00423715) ; 吉松 博信 大分大学, 医学部, 教授 (00166993)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 脂肪肝 / 脾臓摘出 / 炎症性サイトカイン / 脂肪性肝炎 / IL-10 / 過栄養性脂肪肝 / 摂食リズム障害 / 肥満症 / IL-10欠損マウス / 肥満 / ８オキソグアニン / チアゾリジン誘導体 / PPARγ

Research Abstract

In liver of splenectomy-treated diet induced obese rats, the expression of the proinflammatory cytokines induced and the oxystress-induced markers, 8-oxoG and 4-HNE, increased significantly. At 6 months after splenectomy, fibrotic changes were observed in the liver of rats. This result indicates that the loss of spleen contributes to the progression of hepatic steatosis to steatohepatitis in obese rats. These splenectomy-induced changes were inhibited by systemic administration of IL-10. We demonstrated that the spleen-derived IL-10 has a key molecule for the progression of hepatic steatosis to steatohepatitis.

Research Products

• [Journal Article] Obesity-related chronic kidney disease is associated with spleen-derived IL-10 (2013)
  • Author(s): Gotoh K, Inoue M, Masaki T, Chiba S, Shiraishi K, Shimasaki T, Matsuoka K, Ando H, Fujiwara K, Fukunaga N, Aoki K, Nawata T, Katsuragi I, Kakuma T, Seike M, Yoshimatsu H
  • Journal Title: Nephrol Dial Transplant Volume: 28 Pages: 1120-1130
  • Peer Reviewed
• [Journal Article] The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity. (2013)
  • Author(s): Shimasaki T, Masaki T, Mitsutomi K, Ueno D, Gotoh K, Chiba S, Kakuma T, Yoshimatsu H.
  • Journal Title: PLoS One Volume: 8 Issue: 5 Pages: e63626-e63626
  • DOI: 10.1371/journal.pone.0063626
  • Peer Reviewed
• [Journal Article] Spleen-derived interleukin-10 downregulates the severity of high-fat diet-induced non-alcoholic Fatty pancreas disease (2012)
  • Author(s): Gotoh K, Inoue M, Shiraishi K, Masaki T, Chiba S, Mitsutomi K, Shimasaki T, Ando H, Fujiwara K, Katsuragi I, Kakuma T, Seike M, Sakata T, Yoshimatsu H
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced inflammation in white adipose tissue and liver (2012)
  • Author(s): Gotoh K, Inoue M, Masaki T, Chiba S, Shimasaki T, Ando H, Fujiwara K, Katsuragi I, Kakuma T, Seike M, Sakata T, Yoshimatsu H
  • Journal Title: Diabetes Volume: 61 Pages: 1994-2003
  • Peer Reviewed
• [Journal Article] Intraperitoneal administrartion attenuates thiazolidinedions-induced hepatic steatosis in KKAy mice with increased hepatic peroxisome proliferator-activated receptor (PPAR)γ mRNA expression (2012)
  • Author(s): Oribe J, Kakuma T, Haranaka M, Okamoto K, Seike M, Yoshimatsu H
  • Journal Title: Obes Res Clin Prac Volume: 6
  • Peer Reviewed
• [Journal Article] Role of spleen in the development of steatohepatitis in high-fat-diet-induced obese rats (2012)
  • Author(s): Inoue M, Gotoh K, Seike M, Masaki T, Honda K, Kakuma T. Yoshimatsu H
  • Journal Title: Exp Biol Med Volume: 237 Pages: 461-470
  • Peer Reviewed
• [Journal Article] A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced hypothalamic inflammation (2012)
  • Author(s): Gotoh K, Inoue M, Masaki T, Chiba S, Shimasaki T, Ando H, Fujiwara K, Katsuragi I, Kakuma T, Seike M, Sakata T, Yoshimatsu H
  • Journal Title: J Neurochem Volume: 120 Pages: 752-764
  • Peer Reviewed
• [Journal Article] Involvement of remnant spleen volume on the progression of steatohepatitis in diet-induced obese rats after a splenectomy (2012)
  • Author(s): Inoue M, Gotoh K, Seike M, Masaki T, Oribe J, Honda K, Kakuma T. Yoshimatsu H
  • Journal Title: Hepatol Res Volume: 42 Pages: 203-212
  • NAID: 10031144227
  • Peer Reviewed
• [Journal Article] A Novel Anti-Inflammatory Role for Spleen-Derived Interleukin-10 in Obesity-induced Inflammation in White Adipose Tissue and Liver (2012)
  • Author(s): Gotoh K, Inoue M, Masaki T, Chiba S, Shimasaki T, Ando H, Fujiwara K, Katsuragi I, Kakuma T, Seike M, Sakata T, Yoshimatsu H.
  • Journal Title: Diabetes Volume: 61 Issue: 8 Pages: 1994-2003
  • DOI: 10.2337/db11-1688
  • Peer Reviewed
• [Journal Article] Involvement of remnant spleen volume on the progression of steatohepatitis in diet-induced obese rats after a splenectomy. (2012)
  • Author(s): Inoue M, Gotoh K, Seike M, Masaki T, Oribe J, Honda K, Kakuma T, Yoshimatsu H.
  • Journal Title: Hepatol Res. Volume: 42 Issue: 2 Pages: 203-212
  • DOI: 10.1111/j.1872-034x.2011.00914.x
  • NAID: 10031144227
  • Peer Reviewed
• [Presentation] 2型糖尿病治療における血糖と体重の良好なコントロールの両立を目指して (2013)
  • Author(s): 加隈哲也
  • Organizer: 第51回日本糖尿病学会九州地方会
  • Place of Presentation: 那覇
• [Presentation] 肥満に伴う非アルコール性脂肪性肝疾患(NAFLD)の発症における脾臓由来IL-10の役割 (2013)
  • Author(s): 後藤孔郎, 正木孝幸, 千葉政一, 嶋崎貴信, 安藤久恵, 藤原貫為, 加隈哲也, 清家正隆, 柴田洋孝
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京
• [Presentation] 肥満に伴う肝の脂肪化, 炎症性変化およびインスリン抵抗性における脾臓の役割 (2013)
  • Author(s): 後藤孔郎, 井上恵, 白石賢太郎, 安藤久恵, 嶋崎貴信, 正木孝幸, 千葉政一, 藤原貫為, 清家正隆, 加隈哲也
  • Organizer: 第86回日本内分泌学会総会
  • Place of Presentation: 仙台
• [Presentation] 中枢性因子と食行動 (2013)
  • Author(s): 加隈哲也
  • Organizer: 第34回日本肥満学会(シンポジウム)
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] 肥満に伴う視床下部内の慢性炎症における脾臓由来IL-10の役割 (2012)
  • Author(s): 後藤孔郎, 井上恵, 正木孝幸, 千葉政一, 嶋崎貴信, 安藤久恵, 藤原貫為, 葛城功, 加隈哲也, 清家正隆, 坂田利家, 吉松博信
  • Organizer: 第55回日本糖尿病学会総会
  • Place of Presentation: 横浜