PPARγの内因性リガンドの精製と同定

• 研究課題/領域番号: 10877173
• 研究種目: 萌芽的研究
• 配分区分: 補助金
• 研究分野: 代謝学
• 研究機関: 東京大学
• 研究代表者: 戸辺 一之 東京大学, 医学部・附属病院, 助手 (30251242)
• 研究分担者: 鏑木 康志 東京大学, 医学部・附属病院, 医員 ; 山内 敏正 東京大学, 医学部・附属病院, 医員 ; 門脇 孝 東京大学, 医学部・附属病院, 助教授 (30185889) ; 植木 浩二郎 東京大学, 医学部・附属病院, 医員
• 研究期間 (年度): 1998 – 2000
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 1,900千円 (直接経費: 1,900千円); 2000年度: 400千円 (直接経費: 400千円); 1999年度: 600千円 (直接経費: 600千円); 1998年度: 900千円 (直接経費: 900千円)
• キーワード: チアゾリジン誘導体 / PPARファミリー / PPARγのリガンド / 脂質代謝 / インスリン抵抗性 / インスリン受容体 / インスリン受容体基質 / IRS-1 / IRS-2 / IRS-3 / インスリン作用 / 発生工学

研究概要

チアゾリジン誘導体は脂肪細胞に発現しているPPARγに働きかけ脂肪細胞への分化を亢進し、in vivoでインスリン抵抗性を改善する。新たなチアゾリジン誘導体であるKRP-297をZucker fattyラットに投与するとBRL-49,653とは対照的に肝臓においてZucker fattyラットで低下していたパルミチン酸からのCO_2やケトン体産生能が回復することを見出した。また、肝臓での脂質産生や中性脂肪の蓄積の抑制という点でKRP-297はBRL-49,653より効果的であった。次にKRP-297のPPARファミリーの活性化能を検討するとPPARα、PPARγの活性化能のED_<50>はそれぞれ1.0μmol/L、0.8μmol/Lであった。また、PPARα、PPARγへの結合の解離定数はそれぞれ228nmol/Lであった。KRP-297はこれまでのチアゾリジン誘導体とは異なりPPARαに結合しかつPPARαを活性化することが明らかとなった。さらにKRP-297は肝でのacyl-CoA oxidaseの発現及び活性をそれぞれ1.5倍、1.8倍に上昇させた。KRP-297のPPARγの活性化作用はBRL-49,653に比べて弱いが、全身でのインスリン抵抗性改善佐用はBRL-49,653よりも良好である。このことはKRP-297のPPARγの活性化作用が存在し肝臓での脂質代謝改善佐用などを介して全身でのインスリン抵抗性改善作用に関与しているものと思われた(Murakami et al.,Diabetes 47:1841-1847,1998)。

研究成果

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