能量敏感的AMPK-SIRT1通路与炎症调控

Energy-sensitive AMPK-SIRT1 pathway and the regulation of inflammation

腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是参与调节细胞能量代谢的关键激酶,也可通过沉默信息调节因子1(silent information regulator of transcription 1,SIRT1)依赖的途径发挥抗炎效应。AMPK激活SIRT1的机制在于AMPK促进了SIRT1的激活因子NAD+的生成,并解除了DBC1对SIRT1活性及p53对SIRT1表达的抑制效应;而SIRT1则通过催化NF-κB、AP-1和组蛋白的去乙酰化反应而降低转录因子活性、恢复染色质致密构象,这可抑制炎症相关基因的转录。此外,AMPK激活剂及临床常用降糖药二甲双胍均可通过激活AMPK而在多种炎症相关性疾病模型中发挥有效保护作用。因而,AMPKSIRT1通路有望成为抗炎治疗的新靶点。

AMP-activated protein kinase （AMPK） is a crucial kinase involved in the modulation of cellular energy metabolism, and it also has SIRTl-dependent anti-inflammatory activity. The mechanisms through which AMPK activate SIRT1 include promoting the generation of SIRT1 activator NAD＋, relieving the suppressive effects on the activity of SIRT1 by DBC1 and on the expression of SIRT1 by p53. SIRT1 then modulates the inflammatory response through deacetylating nuclear factor kappa B （NF-κB）, activator protein 1 （AP-1） and histones, thus leading to suppressed transcriptional activities of transcription factors, altered conformation of chromatin, and eventually, transcriptional repression of inflammation-related genes. In addition, AMPK activator and the clinic antidiabetic metformin have protective benefits in various animal models with inflammation-related disorders through activating AMPK. Thus, AMPK-SIRTI pathway might become a novel target for anti-inflammatory therapy.