Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Department of Pharmacology, National College of Pharmacy, Kerala University of Health Sciences, Kozhikode, India.
Antiinflamm Antiallergy Agents Med Chem. 2021;20(2):107-117. doi: 10.2174/1871523019666200916115034.
Body defenses and metabolic processes probably co-evolved in such a way that rapid, energy-intensive acute inflammatory repair is functionally integrated with energy allocation in a starvation/ infection / injury-prone primitive environment. Disruptive metabolic surplus, aggravated by sedentary lifestyle induces chronic under-activation of AMPK, the master regulator of intracellular energy homeostasis. Sudden increase in chronic, dysregulated 'sterile' inflammatory disorders probably results from a shift towards calorie rich, sanitized, cushioned, injury/ infection free environment, repositioning inflammatory repair pathways towards chronic, non-microbial, 'sterile', 'low grade', and 'parainflammation'. AMPK, (at the helm of energy provisioning) supervises the metabolic regulation of inflammasome activation, a common denominator in lifestyle disorders.
In this review, we discuss various pathways linking AMPK under-activation and inflammasome activation. AMPK under-activation, the possible norm in energy-rich sedentary lifestyle, could be the central agency that stimulates inflammasome activation by multiple pathways such as 1: decreasing autophagy, and accumulation of intracellular DAMPs, (particulate crystalline molecules, advanced glycation end-products, oxidized lipids, etc.) 2: stimulating a glycolytic shift (pro-inflammatory) in metabolism, 3: promoting NF-kB activation and decreasing Nrf2 activation, 4: increasing reactive oxygen species (ROS) formation, Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) stress.
The 'inverse energy crisis' associated with calorie-rich, sedentary lifestyle, advocates dietary and pharmacological interventions for treating chronic metabolic disorders by overcoming / reversing AMPK under-activation.
身体防御和代谢过程可能是协同进化的，以至于快速、能量密集型的急性炎症修复与在易饥饿/感染/受伤的原始环境中的能量分配在功能上是整合在一起的。代谢过剩的破坏，加上久坐不动的生活方式，加重了 AMPK 的慢性低激活，AMPK 是细胞内能量平衡的主要调节因子。慢性、失调的“无菌”炎症性疾病的突然增加可能是由于向富含卡路里、无菌、舒适、无损伤/感染的环境转变，炎症修复途径向慢性、非微生物、“无菌”、“低度”和“亚炎症”转移所致。AMPK（在提供能量方面处于领先地位）监督着炎症小体激活的代谢调节，炎症小体激活是生活方式紊乱的共同特征。
在这篇综述中，我们讨论了将 AMPK 激活不足与炎症小体激活联系起来的各种途径。AMPK 激活不足，在富含能量的久坐不动的生活方式中可能是正常现象，它可能是通过多种途径刺激炎症小体激活的中枢机构，例如：1：减少自噬和细胞内 DAMPs（颗粒状结晶分子、晚期糖基化终产物、氧化脂质等）的积累；2：刺激代谢的糖酵解转变（促炎）；3：促进 NF-kB 激活和减少 Nrf2 激活；4：增加活性氧（ROS）形成、未折叠蛋白反应（UPR）和内质网（ER）应激。
与富含卡路里、久坐不动的生活方式相关的“反向能量危机”提倡通过克服/逆转 AMPK 激活不足来进行饮食和药物干预，以治疗慢性代谢紊乱。
