PPARbata/delta activation of CD300a controls intestinal immunity

• Project/Area Number: 24650442
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Applied health science
• Research Institution: The University of Tokyo
• Principal Investigator: SAKAI Juro 東京大学, 先端科学技術研究センター, 教授 (80323020)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Toshiya 東京大学, 先端科学技術研究センター, 特任准教授 (20396930)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 生活習慣病 / 腸管免疫 / 核内受容体 / TLR

Research Abstract

we show that PPARbeta/delta (peroxisome proliferator-activated receptor beta/delta) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a-/- mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a-/- macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis.

Research Products

• [Journal Article] PPAR beta/delta activation of CD300a controls intestinal immunity (2014)
  • Author(s): Tanaka T, Tahara-Hanaoka S, Nabekura T, Ikeda K, Jiang S, Tsutsumi S, Inagaki T, Magoori K, Higurashi T, Takahashi H, Tachibana K, Tsurutani Y, Raza S, Anai M, Minami T, Wada Y, Yokote K, Doi T, Hamakubo T, Johan A, J. GF, Nakajima A, Aburatani H, Naito M, Shibuya A, Kodama T, Sakai J
  • Journal Title: Scientific Reports Volume: (in press)
• [Journal Article] Direct evidence of chromatin structure change in KLF4 gene caused by pitavastatin in endothelial cells (2014)
  • Author(s): Maejima T, Tanaka; T, Minami; T, Hamakubo; T, Ihara; S, Sakai; J, Nozaki; N, Aburatani; H, Ruan; X, Tanabe; H, Ruan; Y, Endo; A, Kodama; T, Wada Y
  • Journal Title: PLOS One IMPRESSED Volume: impressed
  • Peer Reviewed
• [Journal Article] Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells (2013)
  • Author(s): Ishimoto K, Tachibana K, Hanano I, Yamasaki D, Nakamura H, Kawai M, Urano Y, Tanaka T, Hamakubo T, Sakai J, Kodama T, Doi T
  • Journal Title: Biochem J Volume: 429 Issue: 2 Pages: 347-357
  • DOI: 10.1042/bj20091511
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase (2013)
  • Author(s): Matsumura Y, Sakai J, Skach WR
  • Journal Title: J Biol Chem Volume: 288 Issue: 43 Pages: 31069-31079
  • DOI: 10.1074/jbc.m113.479345
  • Peer Reviewed
• [Journal Article] Human mannose-binding lectin 2 is directly regulated by peroxisome proliferator-activated receptors (PPARs) via a peroxisome proliferator responsive element (2013)
  • Author(s): Tachibana K, Takeuchi K, Inada H, Sugimoto K, Ishimoto K, Yamashita M, Maegawa T, Yamasaki D, Osada S, Tanaka T, Rakug H, Hamakubo T, Sakai J, Kodama T, Doi T
  • Journal Title: The Journal of Biochemistry Volume: 154 (3) Issue: 3 Pages: 265-73
  • DOI: 10.1093/jb/mvt050
  • Peer Reviewed
• [Journal Article] Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. (2012)
  • Author(s): Mimura I
  • Journal Title: Mol Cell Biol. Volume: Aug;32(15) Issue: 15 Pages: 3018-3032
  • DOI: 10.1128/mcb.06643-11
  • Peer Reviewed
• [Journal Article] Novel repressor regulates insulin sensitivity through interaction with Foxo1 (2012)
  • Author(s): Nakae J, Cao Y, Hakuno F, Takemori H, Kawano Y, Sekioka R, Abe T, Kiyonari H, Tanaka T, Sakai J, Takahashi SI, Itoh H
  • Journal Title: EMBO J. Volume: 31 Issue: 10 Pages: 2275-2295
  • DOI: 10.1038/emboj.2012.97
  • Peer Reviewed
• [Presentation] The immuno-inhibitory receptor CD300A controls intestinal immunity and prevents onset of diabetes through a PPARδdependent pathway (2012)
  • Author(s): Juro Sakai
  • Organizer: 第44回日本動脈硬化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-07-19
• [Presentation] Epigenomic regulation of inflammation, energy metabolism, and adipogenesis (2012)
  • Author(s): Juro Sakai
  • Organizer: The 2012 Deuel Conference on Lipids
  • Place of Presentation: Palm Springs, California
  • Year and Date: 2012-03-08
• [Presentation] JmjC-domain-containing Histone Demethylase 1b is a Novel Regulator of Adipocyte Differentiation (2012)
  • Author(s): 酒井寿郎
  • Organizer: The 35th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 福岡県
  • Invited
• [Presentation] PPARδと腸管免疫ならびに糖脂質代謝の制御 (2012)
  • Author(s): 酒井寿郎
  • Organizer: 脳心血管抗加齢研究会2012
  • Place of Presentation: 大阪府
  • Invited
• [Presentation] Epigenomic Regulation of Inflammation, Energy Metabolism and Adipogenesis
  • Author(s): 酒井 寿郎
  • Organizer: Key Stone Symposia 2013 （招待講演）
  • Place of Presentation: Alpbach, Austria
  • Invited
• [Presentation] Epigenomic Regulation of Energy Metabolism and Obesity
  • Author(s): 酒井 寿郎
  • Organizer: 7th Asia Oceania Conference of Obesity （招待講演）
  • Place of Presentation: Bandung, Indonesia
  • Invited
• [Presentation] Epigenomic Regulation of Energy Metabolism in Brown Adipocytes through Phosphorylation of Histone Demethylase Jmjd1a
  • Author(s): 酒井 寿郎
  • Organizer: Nuclear Receptors & Diseases（招待講演）
  • Place of Presentation: Suzhou, China
  • Invited
• [Presentation] ヒストン脱メチル化酵素Jmjd1aと肥満・メタボリックシンドローム
  • Author(s): 酒井 寿郎
  • Organizer: 第60回日本実験動物学会総会（招待講演）
  • Place of Presentation: 筑波
  • Invited
• [Presentation] ヒストン脱メチル化酵素Jmjd1aの翻訳後修飾によるメタボリックシンドローム発症機構
  • Author(s): 酒井 寿郎
  • Organizer: 第56回日本糖尿病学会年次学術集会（招待講演）
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 生活習慣病、分子遺伝学からエピゲノミックスへ
  • Author(s): 酒井 寿郎
  • Organizer: 第38回日本化粧品学会（招待講演）
  • Place of Presentation: 東京
  • Invited
• [Presentation] 肥満・生活習慣病発症におけるヒストン脱メチル化酵素Jmjd1aと交換神経経路の役割
  • Author(s): 酒井 寿郎
  • Organizer: 第2回日本DOHaD研究会年会（招待講演）
  • Place of Presentation: 東京
  • Invited
• [Presentation] Epigenomic Regulation of Energy Metabolism in Brown Adipocytes and Metabolic syndrome
  • Author(s): 酒井 寿郎
  • Organizer: 第45回日本動脈硬化学会総会・学術集会（招待講演）
  • Place of Presentation: 東京
  • Invited
• [Presentation] ヒストン脱メチル化酵素の翻訳後修飾と肥満・メタボリックシンドローム
  • Author(s): 酒井 寿郎
  • Organizer: 脳心血管抗加齢研究会2013（招待講演）
  • Place of Presentation: 大阪
  • Invited
• [Remarks]
  • URL: http://www.mm.rcast.u-tokyo.ac.jp/
• [Remarks] 東京大学先端科学技術研究センター代謝医学酒井研究室/原著論文
  • URL: http://www.mm.rcast.u-tokyo.ac.jp/
• [Remarks] 東大先端科学技術研究センター 代謝医学分野 酒井研究室 業績集
  • URL: http://www.mm.rcast.u-tokyo.ac.jp/publications/pubs.html