Choudhury Asmita, Mandrekar Pranoti
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Curr Pathobiol Rep. 2020 Sep;8(3):47-59. doi: 10.1007/s40139-020-00211-z. Epub 2020 Jul 17.
Alcohol associated liver disease (ALD) accounts for significant mortality and morbidity in the United States. Prolonged alcohol exposure leads to increased reactive oxygen species and oxidative stress resulting in protein misfolding and/or aggregation. Cellular protein homeostasis network is an adaptive cellular response comprised of machineries that regulate biogenesis or degradation of proteins with chaperones as central coordinators to maintain proteome integrity during stress. Two extensively studied organelle-specific transcriptional proteostasis pathways are the heat shock response (HSR) in the cytosol and unfolded protein response (UPR) in endoplasmic reticulum (ER). Here we review the pathophysiological role of HSR and UPR and their potential as therapeutic targets in ALD.
The HSR and UPR are emerging as important pathways in ALD pathogenesis. We reported that acute and chronic alcohol activate the HSR to discretely induce downstream target chaperones, HSPA1A/HSP70 and HSP90, respectively. HSP90 serves as a pro-inflammatory mediator in ALD by stabilizing client kinases and adapters. On the other hand, HSF1 and HSPA1A prevents liver injury due to their anti-inflammatory properties. In vivo pharmacological targeting of HSP90 reduced pro-inflammatory cytokines and NLRP3 inflammasome mediated IL-1β and IL-18. The presence of HSP90 in circulating extracellular vesicles in ALD mouse models suggests its role in pathogenesis. Activation of UPR due to prolonged ER stress is associated with apoptosis, inflammation, and lipogenesis contributing to liver injury.
This review highlights the contribution of HSR and UPR, as well as druggable chaperones in pathogenesis of ALD. Binge/moderate or chronic alcohol exposure perturbs proteostasis mediators which fail to maintain proteome integrity and disease ensues. Understanding mechanisms that regulate proteostasis pathways, HSR and UPR, could identify novel disease modulators and guide development of therapeutic targets in ALD.
酒精性肝病（ALD）在美国导致了显著的死亡率和发病率。长期饮酒会导致活性氧和氧化应激增加，从而导致蛋白质错误折叠和/或聚集。细胞蛋白质稳态网络是一种适应性细胞反应，由调节蛋白质生物合成或降解的机制组成，伴侣蛋白作为中心协调者，在应激期间维持蛋白质组的完整性。两个被广泛研究的细胞器特异性转录蛋白质稳态途径是细胞质中的热休克反应（HSR）和内质网（ER）中的未折叠蛋白反应（UPR）。在此，我们综述HSR和UPR的病理生理作用及其作为ALD治疗靶点的潜力。
HSR和UPR正在成为ALD发病机制中的重要途径。我们报道，急性和慢性酒精分别激活HSR以离散地诱导下游靶伴侣蛋白HSPA1A/HSP70和HSP90。HSP90通过稳定客户激酶和衔接蛋白，在ALD中作为促炎介质发挥作用。另一方面，HSF1和HSPA1A因其抗炎特性而预防肝损伤。在体内对HSP90进行药理学靶向可减少促炎细胞因子和NLRP3炎性小体介导的IL-1β和IL-18。在ALD小鼠模型的循环细胞外囊泡中存在HSP90，表明其在发病机制中的作用。由于内质网长期应激导致的UPR激活与细胞凋亡、炎症和脂肪生成有关，从而导致肝损伤。
本综述强调了HSR和UPR以及可药物靶向的伴侣蛋白在ALD发病机制中的作用。暴饮/适度或慢性酒精暴露会扰乱蛋白质稳态介质，这些介质无法维持蛋白质组的完整性，从而引发疾病。了解调节蛋白质稳态途径HSR和UPR的机制，可能会识别出新的疾病调节因子，并指导ALD治疗靶点的开发。
