核受容体依存のフォスファディチルコリン経路で,抗糖尿病効果があります
Jae Man Lee1, Yoon Kwang Lee, Jennifer L Mamrosh
1Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature
|May 27, 2011
まとめ
新しいフォスファディチルコリン,ディラウロイルフォスファディチルコリン (DLPC) はLRH-1アゴニストとして作用します. この発見は,胆酸代謝,肝臓トリグリセリド,およびグルコースホメオスタシスを調節する新しいシグナル伝達経路を明らかにしています.
科学分野:
- 内分泌学 エンドックリノロジー
- メタボリック疾患
- 分子生物学は分子生物学である.
背景:
- LRH-1 (NR5A2) を含む核ホルモン受容体は,代謝経路の重要な調節体である.
- フォスフォリピドはLRH-1のリガンドとして提案されているが,その機能的意義は不明である.
研究 の 目的:
- LRH-1リガンドとしてのフォスフォリピドの機能的役割を調査する.
- LRH-1を活性化させ,その代謝効果を解明する特定のフォスフォリピド種を特定する.
主な方法:
- フォスファディチルコリン種のLRH-1アゴニスト活性を特定するためのインビトロアッセイ.
- マウスモデルを用いたインビボ試験で,DLPCが胆酸バイオシンセシス,肝臓トリグリセリド,血清グルコース,およびインスリン抵抗性に対する影響を評価した.
- 肝臓特異的なLrh-1ノックアウトマウスを用いて,LRH-1依存性を確認した.
主要な成果:
- ディラウロイルフォスファティディルコリン (DLPC) は,LRH-1アゴニストとしてインビトロで特定されました.
- ネズミにDLPCを投与すると,胆酸レベルが上昇し,胆酸合成に関与する肝臓酵素が誘発される.
- DLPC治療は,インスリン抵抗性のマウスモデルにおける肝臓トリグリセリド,血清グルコース,肝臓ステアトーシスおよび改善されたグルコースホメオスタシスを減少させました.
- これらの有益な効果は,肝臓特異的なLrh-1ノックアウトマウスで廃止されました.
結論:
- DLPCによって媒介される新しいLRH-1依存シグナル伝達経路は,胆酸代謝を調節する.
- この経路は,グルコースホメオスタシスと脂質代謝の維持に重要な役割を果たします.
- DLPCは,インスリン抵抗性や2型糖尿病などの代謝障害の潜在的治療目標です.
関連する概念動画
01:28Insulin: The Receptor and Signaling Pathways
Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:25cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
01:31Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
01:27Synthesis of Phosphatidylcholine in the ER Membrane
The ER synthesizes lipids for building cell membranes and performing cellular functions such as energy storage and signaling. The lipid synthesis machinery embedded in the ER membrane primarily collects all reactants from the cytosol. Following synthesis, the secretory pathway and the ER contact sites distribute these lipids to other cellular organelles. Additionally, the energy-rich triacylglycerides are transported from the ER via lipid droplets.
The major components of all eukaryotic cell...
The major components of all eukaryotic cell...