Wang Minghan, Tafuri Sherrie
Department of Molecular Sciences, Pfizer Global Research and Development Ann Arbor Laboratories, 2800 Plymouth Road, Michigan 48105, USA.
J Cell Biochem. 2003 May 1;89(1):38-47. doi: 10.1002/jcb.10492.
The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a member of the ligand-activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARgamma, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin-sensitizing activities as well as tissue selectivity of PPARgamma activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARgamma activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti-atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARgamma agonists can be potentially employed for the treatment of atherosclerosis in general population.
抗糖尿病噻唑烷二酮类药物（TZDs）是一类具有胰岛素增敏活性的化合物，最初是通过体内药理学筛选发现的。在随后的结合研究中，TZDs被证明可通过激活过氧化物酶体增殖物激活受体γ（PPARγ）来增强胰岛素作用。PPARγ是配体激活的核受体超家族的成员，通过控制葡萄糖和脂质代谢相关基因的表达促进脂肪生成并增强胰岛素敏感性。鉴于PPARγ中配体结合口袋较大，已发现了结构上与TZDs不同的新型完全激动剂和部分激动剂。这些化合物在区分脂肪生成和胰岛素增敏活性以及PPARγ激活的组织选择性方面是有效的工具。这些信息导致了这样一种假设，即一种配体可以根据PPAR所在的组织激活或失活PPAR。因此，特定的化合物可以被指定为选择性PPAR调节剂或SPPARMs，这一概念类似于选择性雌激素受体调节剂（SERMs）对雌激素受体（ER）的激活。此外，临床前和临床数据均表明PPARγ激活对预防动脉粥样硬化有用。然而，TZDs对血浆脂质谱的影响并不能完全解释其抗动脉粥样硬化作用。最近对巨噬细胞和动脉粥样硬化动物模型的研究表明，TZDs通过调节巨噬细胞的泡沫细胞形成和炎症反应来减少血管壁中形成的病变的大小和数量。因此，除了治疗II型糖尿病外，PPARγ激动剂通常还可用于治疗普通人群的动脉粥样硬化。
