Hotamisligil Gökhan S, Davis Roger J
Department of Genetics and Complex Diseases, Broad Institute of Harvard-MIT, Harvard School of Public Health, Boston, Massachusetts 02115.
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Cold Spring Harb Perspect Biol. 2016 Oct 3;8(10):a006072. doi: 10.1101/cshperspect.a006072.
Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These pathways are also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress and leads to a compensatory increase in ER function. The JNK and p38 MAPK signaling pathways control adaptive responses to intracellular and extracellular stresses, including environmental changes such as UV light, heat, and hyperosmotic conditions, and exposure to inflammatory cytokines. Metabolic stress caused by a high-fat diet represents an example of a stimulus that coordinately activates both the UPR and JNK/p38 signaling pathways. Chronic activation of these stress-response pathways ultimately causes metabolic changes associated with obesity and altered insulin sensitivity. Stress-signaling pathways, therefore, represent potential targets for therapeutic intervention in the metabolic stress response and other disease processes.
应激信号通路在进化上是保守的，在维持体内平衡中发挥重要作用。这些通路对于适应新的细胞环境也至关重要。内质网（ER）未折叠蛋白反应（UPR）由生物合成应激激活，并导致ER功能的代偿性增加。JNK和p38 MAPK信号通路控制对细胞内和细胞外应激的适应性反应，包括紫外线、热和高渗条件等环境变化，以及接触炎性细胞因子。高脂饮食引起的代谢应激是一种能同时激活UPR和JNK/p38信号通路的刺激的例子。这些应激反应通路的慢性激活最终会导致与肥胖相关的代谢变化以及胰岛素敏感性改变。因此，应激信号通路是代谢应激反应和其他疾病过程中治疗干预的潜在靶点。
