Harnessing the Proteostasis Network in Alcohol-associated Liver Disease.

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.