Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
Curr Drug Targets. 2018;19(6):663-673. doi: 10.2174/1389450118666170622091333.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor. It regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are potent insulin sensitizers that function by activating PPARs, with a high specificity for PPARγ. Due to their ability to preserve pancreatic beta cell function and reduce insulin resistance, TZDs have become one of the most prescribed classes of medications for type 2 diabetes (T2D) since their approval by the US Food and Drug Administration (FDA) and initial use in 1997.
However, adverse effects, including weight gain, bone loss, fluid retention, congestive heart failure, and risk to bladder cancer, have weakened the benefits of TZDs in T2D therapies. Therefore, there is an urgent need to have a deeper understanding of regulatory mechanisms of PPARγ expression and activity so that novel classes of PPARγ-modulating therapeutics with fewer or weaker side effects can be developed.
This article systematically reviews PPARγ's mechanisms of action and multilayer regulations. In addition, novel classes of therapeutics modulating PPARγ and new direction of research on genetic variants that affect PPARγ function and antidiabetic drug response are highlighted, which sheds light on PPARγ as a promising target for developing safer and precision medicine based therapeutic strategies.
过氧化物酶体增殖物激活受体 γ (PPARγ) 是核受体超家族的成员，作为配体诱导型转录因子发挥作用。它调节葡萄糖和脂质代谢、免疫以及细胞生长和分化。噻唑烷二酮类 (TZDs) 是一种有效的胰岛素增敏剂，通过激活 PPARs 发挥作用，对 PPARγ 具有高度特异性。由于它们能够保护胰岛β细胞功能并降低胰岛素抵抗，因此自美国食品和药物管理局 (FDA) 批准并于 1997 年首次使用以来，TZDs 已成为治疗 2 型糖尿病 (T2D) 最常用的药物类别之一。
然而，不良反应，包括体重增加、骨丢失、体液潴留、充血性心力衰竭和膀胱癌风险，削弱了 TZDs 在 T2D 治疗中的益处。因此，迫切需要更深入地了解 PPARγ 表达和活性的调节机制，以便开发出具有更少或更弱副作用的新型 PPARγ 调节治疗药物。
本文系统综述了 PPARγ 的作用机制和多层次调控。此外，还强调了新型调节 PPARγ 的治疗药物和影响 PPARγ 功能和抗糖尿病药物反应的遗传变异的新研究方向，为开发更安全和精准的基于 PPARγ 的治疗策略提供了启示。
