Investigation of Novel Function and Its Relation to Diseases for New Taget Proteins to Which Sulfonylureas Bind

我们发现，格列本脲，一种典型的抗糖尿病磺酰脲类药物，结合和光标记的CD 36，而不是磺酰脲类受体在心脏组织中，因为它的受体的亲和力低于相应的胰腺对应物。在这个项目中，我们首先旨在揭示磺脲类药物对巨噬细胞中CD 36的功能影响。格列本脲以剂量依赖性方式抑制巨噬细胞和CD 36转染CHO细胞中氧化LDL通过CD 36的结合、结合和解离过程。其他磺酰脲类药物也抑制这些过程，但格列本脲是测试化合物中最有效的。磺酰脲类药物是否影响脂质代谢尚不清楚，因此我们研究了磺酰脲类药物对胆固醇代谢的影响。我们发现，格列本脲也抑制巨噬细胞中酰基辅酶A：胆固醇酰基转移酶（ACAT）的活性。抑制作用不如CI-976和NTE-122（典型的ACAT抑制剂）有效，但在存在100 μM格列本脲时，抑制作用完全。这些结果表明，磺酰脲类药物不仅可以作为氧化LDL通过CD 36摄取的抑制剂，而且还可以作为ACAT抑制剂，尽管化学结构与常规抑制剂有很大不同，这表明它们可以成为产生新的潜在脂质代谢抑制剂的种子。

We found out that glibenclamide, a typical antidiabetic sulfonylurea, bound and photolabel CD36 instead of sulfonylurea receptors in cardiac tissues, since its affinity for the receptors was lower than the corresponding pancreatic counterparts. In this project we first aim to reveal functional effects of sulfonylureas on CD36 in macrophages. Glibenclamide inhibited the binding, association, and dissociation processes of oxidized LDL via CD36 in macrophages and CD36-transfected CHO cells in dose-dependent manners. Other sulfonylureas also inhibited those processes but glibenclamide was the most effective among the compounds tested. Little has been known whether sulfonylureas affect the lipid metabolism and we then investgated their effects on cholesterol metabolism. We discovered that glibenclamide also inhibited the activity of acyl CoA: cholesterol acyltransferase (ACAT) in macrophages. The inhibition was not so much effective as those by CI-976 and NTE-122, typical ACAT inhibitors but the inhibition was complete in the presence of 100 μM glibenclamide. These results indicate that sulfonylureas act as not only inhibitor for oxidized LDL uptake via CD36 but also ACAT inhibitor, although chemical structures are quite different from conventional inhibitors, suggesting that they can be seeds to generate new potential inhibitors for the lipid metabolism.