Stress management: How the unfolded protein response impacts fatty liver disease

Abstract

Summary Induction of the unfolded protein response (UPR) is recognized as central to fatty liver disease (FLD) pathophysiology. This pathway may be a potential therapeutic target for FLD, as well as other diseases. However, fundamental questions as to how UPR contributes to FLD remain unanswered. Conflicting data suggest that this pathway can both protect against and augment this disease. Here, we review the relationship between protein secretion, endoplasmic reticulum function (ER), and UPR activation. The UPR serves to maintain secretory pathway homeostasis by enhancing the protein folding environment in the ER, and we review data investigating the role for individual UPR players in fatty liver (steatosis). We explore a novel concept in the field that all cases of UPR activation do not equal “ER stress”. Rather, different types of UPRs that can either protect against or cause FLD are discussed. Refining our current understanding of this complex pathway is particularly important, as drugs that affect the protein folding environment in the ER and affect UPR activation are being successful in clinical trials for FLD.

Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in alcoholic liver disease

“…S2B). We speculate that the biphasic nature of target gene activation and xbp1 splicing reflects the transition from an adaptive UPR (at 2–12 hours) to a stressed UPR (24 hours and beyond) (Imrie and Sadler, 2012). …”

“…For instance, we and others have demonstrated that ER stress induced by blocking protein glycosylation with tunicamycin is sufficient to cause steatosis (Cinaroglu et al, 2011; Henkel et al, 2009; Imrie and Sadler, 2012; Malhi and Kaufman, 2011; Puri et al, 2008; Rinella et al, 2011). However, whether the same constellation of UPR targets and effectors that become activated in this robust ER stress are also active in response to ethanol is not clear.…”

“…The UPR is a complex pathway that serves to enhance and restore the protein-folding and secretory capacity of the ER (Walter and Ron, 2011). ER stress refers to sustained UPR activation due to unmitigated accumulation of unfolded proteins in the ER, reflecting organelle dysfunction that can result in steatosis and apoptosis (Imrie and Sadler, 2012). In contrast, moderate UPR activity is beneficial because it augments protein secretion and can serve as an adaptive mechanism to protect cells that are repeatedly stressed (Rutkowski and Kaufman, 2007).…”

“…Several studies point to a role for chronic UPR activation as a causative factor for steatosis in multiple etiologies of fatty liver disease (Cinaroglu et al, 2011; Henkel et al, 2009; Imrie and Sadler, 2012; Malhi and Kaufman, 2011; Puri et al, 2008; Rinella et al, 2011). Although the mechanistic link between the UPR induction and lipid metabolism is unknown, these studies suggest that UPR activation could be a widespread mechanism of steatosis.…”

Zebrafish: An Important Tool for Liver Disease Research

“…82 Atf6 overexpression was sufficient to cause fatty liver in zebrafish under stress-free conditions. 82 This finding is significant because UPR induction and ER stress are possible mechanisms of FLD of many etiologies 83 and have been proposed as therapeutic targets, but until this study, the direct cause of FLD by a UPR player had not been clearly shown. Further studies are required before these findings can be tested in patients, because atf6 disruption only reduced steatosis caused by prolonged stress; in contrast, Atf6 loss increased steatosis in acute stress models of FLD.…”