Lysosome and proteasome dysfunction in alcohol-induced liver injury

Abstract This review presented herein describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes: the lysosome and the ubiquitin-proteasome system (UPS). The lysosome is a membrane-bound organelle that degrades all aging and/or damaged organelles and hydrolyzes all forms of macromolecules. The UPS is mostly proteolytic. It carries out the majority of its functions in the soluble portion of the cytoplasm (cytosol) and degrades nearly all intracellular proteins, particularly those with short half-lives, so that their levels are tightly controlled. Our review will briefly discuss the epidemiology of alcohol abuse and the spectrum of alcohol-induced liver disease (AILD). We will explain why ethanol (EtOH) metabolism, but not EtOH alone, is hepatotoxic. Then, we will summarize how heavy drinking alters hepatic catabolic systems, resulting in liver enlargement that develops from hepatocyte swelling due, in part, to aberrant accumulation of undegraded lipid droplets (steatosis) and undegraded proteins (proteopathy). Our detailed description of each catabolic system will highlight its discoverer(s) and emphasize each system’s characteristics. Most important, we will review the evidence that chronic EtOH consumption disrupts hepatic lysosome biogenesis and inhibits the UPS by impeding hepatic proteasome activity. It will become evident that each of these EtOH-induced defects has far-reaching functional consequences. Finally, we will describe current and potential therapeutic interventions for alleviating EtOH-induced liver injury. The most effective intervention is the cessation of EtOH consumption. However, there are other potential approaches using natural or synthetic compounds that activate autophagy or the proteasome to enhance the degradation of accumulated lipid droplets or proteins, respectively, which could alleviate AILD. These approaches, now in their early stages of investigation, will also be discussed in this review.