Efflux proteins and insulin resistance in atherogenesis

CD36是一种广泛表达的88kD跨膜糖蛋白，是一种清道夫受体、黏附和信号分子，也是脂肪酸转运的促进剂。我们和其他人之前的工作确定CD36是巨噬细胞泡沫细胞形成和动脉粥样硬化形成的主要介质。最近，出现了一个悖论：在CD36基因缺失的实验条件下，以及当CD36通过药物手段上调时，观察到了显著防止病变发展和进展的保护作用。利用干细胞移植CD36/apoE骨髓进入apoE缺陷区 在动物实验中，我们发现完全缺乏CD36所提供的动脉粥样硬化保护作用还没有完全实现。因此，这一应用的一个主要假设是CD36具有独立于其清道夫受体作用的动脉粥样硬化保护特性。基于新出现的数据，我们着重于CD36在外排途径和调节胰岛素抵抗中的作用，这两者都是由激活PPAR的药物刺激的，PPAR是调节CD36表达的转录因子。我们假设CD36在维持血管壁内稳态中起关键作用，而通过CD36进入巨噬细胞的胆固醇有助于促进促动脉粥样硬化的修饰低密度脂蛋白从内膜中清除，并最终允许脂质通过外流途径清除。CD36调控与主要外排途径关系的阐明 是我们研究的一个主要目标。胰岛素抵抗是动脉粥样硬化形成的一个单独的危险因素，并导致其过早发展。我们推测CD36在动脉粥样硬化形成中的部分保护作用与其对葡萄糖和脂肪酸代谢的影响有关。我们将利用现有的独特动物模型，根据清道夫受体的功能或其作为脂肪酸运输促进剂和胰岛素敏感性决定因素的作用，来探索CD36在动脉粥样硬化中的不同影响。这些方法将使我们能够设计更具体的治疗方案，最终将对人类健康和疾病产生影响。

CD36 is a broadly expressed 88 kD transmembrane glycoprotein which functions as a scavenger receptor, adhesion and signaling molecule and a facilitator of fatty acid transport. Previous work by our group and others determined that CD36 was a major mediator of macrophage foam cell formation and atherogenesis. Recently, a paradox has emerged: significant protection against lesion development and progression was observed in experimental conditions where CD36 was rendered absent genetically and when CD36 was upregulated by pharmacological means. Using stem cell transfer of CD36/apoE bone marrow into apoE null animals, we found that the atheroprotective effect afforded by complete absence of CD36 was not fully realized. Thus, a major hypothesis of this application is that CD36 has atheroprotective properties independent of its role as a scavenger receptor. Based on emerging data, we focus on the role of CD36 in efflux pathways and in modulating insulin-resistance, both of which are stimulated by drugs which activate PPARs, transcription factors which regulate CD36 expression. We hypothesize that CD36 is a critical player in maintenance of vessel wall homeostasis, and that entry of cholesterol into macrophages via CD36 facilitates removal of pro-atherogenic modified LDL from the intima, and ultimately allows lipid clearance through efflux pathways. Elucidation of the regulation of CD36 in relationship to the major efflux pathways is a major goal of our studies. Insulin resistance is a separate risk factor for atherogenesis and results in its premature development. We hypothesize that a portion of the protective role of CD36 in atherogenesis is related to its effect on glucose and fatty acid metabolism. We will utilize unique animal models we have on hand to explore the differential impact of CD36 on atherosclerosis based on scavenger receptor function or its role as a facilitator of fatty acid transport and determinant of insulin sensitivity. These approaches will enable us to design more specific treatment regimens which will ultimately impact on human health and disease.