Molecular basis for cell-type specific HDL generation by selective LXR modulators

• Project/Area Number: 20590116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: National Institute of Health Sciences
• Principal Investigator: MOGAMI Tomoko National Institute of Health Sciences, 機能生化学部, 室長 (90174333)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 核内受容体 / LXR / HDL / 選択的モジュレーター / ABCA1 / PPARγ / RXR

Research Abstract

Nuclear receptor LXR stimulates HDL-generating ABC transporter A1 (ABCA1) expression. However, because LXR also enhances lipogenesis, cell-type or gene-selective LXR modulates may be promising strategies. We previously identified Riccardin C as a LXRα agonist/LXRβ antagonist that functions as a cell-type selective modulator. In this study, we investigated molecular basis of selective LXR/RXR modulators and showed the followings. Helix 3-7 of LXRα and Ala327 in this region play critical roles in Riccardin C-induced LXRα transactivation. The RXR agonists PA024, HX630, and tributyltin have different abilities to activate LXR/RXR, resulting in cell-type specific inductions of ABCA1 expression and HDL generation.

Research Products

• [Journal Article] Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRalpha/RXR. (2011)
  • Author(s): Cui H, Okuhira K, Ohoka N, Naito M, Kagechika H, Hirose A, Nishimaki-Mogami T
  • Journal Title: Biochem Pharmacol. 81 Pages: 819-824
• [Journal Article] Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRalpha/RXR. (2011)
  • Author(s): Cui H, et al.
  • Journal Title: Biochem Pharmacol. Volume: 81 Pages: 819-824
  • Peer Reviewed
• [Journal Article] Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation. (2010)
  • Author(s): Okuhira K, Fitzgerald ML, Tamehiro N, Ohoka N, Suzuki K, Sawada JI, Naito M, Nishimaki-Mogami T
  • Journal Title: J Biol Chem 285 Pages: 16369-16377
• [Journal Article] HDL産生トランスポーターABCA1の肝での二重転写制御機構生化学 (2010)
  • Author(s): 最上(西巻)知子
  • Journal Title: 82 Pages: 852-856
• [Journal Article] Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation. (2010)
  • Author(s): Okuhira K, et al
  • Journal Title: J Biol Chem Volume: 285 Pages: 16369-16377
  • Peer Reviewed
• [Journal Article] HDL産生トランスポーターABCA1の肝での二重転写制御機構 (2010)
  • Author(s): 最上(西巻)知子
  • Journal Title: 生化学 Volume: 82 Pages: 852-856
• [Journal Article] The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines. (2008)
  • Author(s): Nishimaki-Mogami T, Tamehiro N, Sato Y, Okuhira K, Sai K, Kagechika H, Shudo K, Abe-Dohmae S, Yokoyama S, Inoue K, Sawada J
  • Journal Title: Biochem Pharmacol 76 Pages: 1006-1013
• [Journal Article] The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines (2008)
  • Author(s): Nishimaki-Mogami T, et al
  • Journal Title: Biochem Pharmacol 76 Pages: 1006-1013
  • Peer Reviewed
• [Presentation] Regulation of human hepatic ABCA1 gene expression by sterols (2010)
  • Author(s): Tomoko Nishimaki-Mogami
  • Organizer: 第42回日本動脈硬化学会総会シンポジウム
  • Place of Presentation: 岐阜市
  • Year and Date: 2010-07-15
• [Presentation] Regulation of human hepatic ABCA1 gene expression by sterols (2010)
  • Author(s): 最上(西巻)知子
  • Organizer: 第42回日本動脈硬化学会総会(シンポジウム)
• [Presentation] Liver X receptor(LXR)modulators : potential therapeutic agents for raising HDL levels and protecting against atherosclerosis (2009)
  • Author(s): Tomoko Nishimaki-Mogami
  • Organizer: 第41回日本動脈硬化学会総会シンポジウム
  • Place of Presentation: 山口市
  • Year and Date: 2009-07-18
• [Presentation] Liver X receptor (LXR) modulators : potential therapeutic agents for raising HDL levels and protecting against atherosclerosis (2009)
  • Author(s): 最上(西巻)知子
  • Organizer: 第41回日本動脈硬化学会総会(シンポジウム)
• [Presentation] 核内レセプターと胆汁酸・脂質代謝 (2008)
  • Author(s): 最上(西巻)知子
  • Organizer: 第30回胆汁酸研究会サテライトシンポジウム