Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation
Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation
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DOI：
10.3945/ajcn.2009.28449e
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发表时间：
2010-01-01
影响因子：
7.1
通讯作者：
DePaoli, Alex M.
中科院分区：
文献类型：
--
作者：
Higgins, Linda Slanec;DePaoli, Alex M.
过氧化物酶体增殖物激活受体γ(PPARγ)是治疗胰岛素抵抗的临床有效靶点。在2型糖尿病患者中，由噻唑烷二酮等完全激动剂激活的PPAR伽马显示出强大而持久的降糖活性，而无需担心与用于治疗这种疾病的其他药物相关的低血糖或胃肠道毒性。然而，噻唑烷二酮类药物与安全性和耐受性问题有关，如体重增加、液体滞留、水肿、充血性心力衰竭和骨折。PPAR伽马的独特特性为选择性调节受体提供了机会，从而可以在没有完全激活的不必要影响的情况下获得所需的治疗效果。PPARγ是一种核受体，它与辅助受体RXR和细胞类型和细胞状态特定的辅助调节因子阵列形成复合体，以控制基因转录。这些组分的PPAR伽马亲和力，从而转录反应，是由具有多个相互作用点的复杂口袋中的配体结合引起的构象变化决定的。因此，这种分子机制为选择性调节提供了机会。一个理想的选择性PPAR伽马调节剂配置文件将包括与PPAR伽马结合口袋的高亲和力相互作用，以导致保留以完全激动剂为特征的胰岛素增敏活性，以及缓解导致肥胖症增加、液体滞留、充血性心力衰竭和骨折的影响。已经确定了内源性和合成选择性PPAR伽马调节剂(SPPARM)配体的例子。SPPARM候选药物正在进行临床测试，并为这一战略提供支持。Am J Clin Nutr 2010；91(Suppl)：267S-72S。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a clinically validated target for treatment of insulin resistance. PPAR gamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPAR gamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPAR gamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type-and cell state specific array of coregulators to control gene transcription. PPAR gamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPAR gamma modulator profile would include high-affinity interaction with the PPAR gamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPAR gamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy. Am J Clin Nutr 2010; 91(suppl):267S-72S.