Harnessing the Proteostasis Network in Alcohol-associated Liver Disease

AbstractPurpose of ReviewAlcohol-associated liver disease (ALD) accounts for significant mortality and morbidity in the USA. 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 that regulates 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 the endoplasmic reticulum (ER). Here, we discuss the pathophysiological role of HSR and UPR and their potential as therapeutic targets in ALD.Recent FindingsThe HSR and UPR pathways are major players in ALD pathogenesis. Acute/binge and chronic alcohol can activate the HSR to selectively induce downstream target chaperones based on the duration of alcohol exposure. Molecular chaperone HSP90 contributes to pro-inflammatory responses in ALD. Recent findings report HSP90 in extracellular vesicles in ALD suggesting their role in cellular communication and disease progression. Extensive studies have reported UPR activation due to ER stress resulting in hepatocyte cell death, inflammation, and lipogenesis contributing to liver injury. Recent studies report that ER stress plays a role in neutrophil-mediated liver injury in ALD.SummaryThis review hig...

Source: Current Pathobiology Reports - July 16, 2020 Category: Laboratory Medicine Source Type: research