Endoplasmic reticulum stress in liver diseases

Abstract

The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis ("adaptive UPR"), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained ("maladaptive UPR"). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.

Fig. 1.. Mild ER Stress And Adaptive UPR

Mild ER stress triggers adaptive UPR signalings that consist of three main branches including PERK, IRE1, and ATF6α. PERK mediates phosphorylation of eIF2α that participates in autophagy of the ER (reticulophagy) through a selective translation of ATG12. Also, PERK mediates selective translation of ATF4 that translocates to the nucleus and transactivates UPR-target genes associated with autophagy induction and alleviation of ER stress. Besides, PERK activates the PIK3CA-AKT1 axis to suppress apoptosis. Moreover, PERK turns on MAPK signaling, which inhibits BAD-mediated apoptosis, and activates NFE2L2 that translocates to the nucleus and transactivates genes associated with autophagy and ROS inhibition. Similarly, IRE1 triggers pathways to block BAD-mediated apoptosis. Importantly, IRE1 induces activation of MAPK8 that translocates to the nucleus and upregulates autophagy genes. Likewise, IRE1-activated XBP1s translocates to the nucleus and transactivates autophagy and ERAD-related genes. Finally, ATF6α is cleaved and activated in the Golgi then translocates to the nucleus to mildly upregulate CHOP, resulting in mild autophagy. It is noteworthy that ULK1 forms an autophagy initiation complex, which is regulated by MTORC1, as ULK1 phosphorylation renders ULK1 inactivation and autophagy inhibition (5).

Fig. 2.. Severe ER Stress Triggers Maladaptive UPR

Severe ER stress triggers maladaptive UPR, leading to activation of cell death. Hyperactivated PERK triggers overexpression of NFE2L2-/ATF4-target genes leading to excessive autophagy, cell death, and CHOP-mediated apoptosis. Also, hyperactivation of IRE1 induces apoptosis via CASP2 activation. Hyperactivated MAPK8 and XBP1s induce overexpression of autophagy genes, resulting in excessive autophagy. Similarly, hyperactivation of ATF6α induces overexpression of proapoptotic factors and autophagy genes, ultimately, leading to cell death (5).

Fig. 3.. Small Molecules Targeting UPR Branches

List of small chemicals for specific targeting of UPR components (129, 130). Given that the majority of these compounds have not been examined in the context of liver diseases, future studies are warranted to examine these compounds in the context of liver disease in both pre-clinical and clinical studies.

Fig. 4.. Targeting ER Stress In Liver Diseases

Overall, pharmaceutical and natural agents, physical exercise, and caloric restriction diminish ER stress, and therefore, alleviate non-malignant liver diseases. Pharmaceutical agents suppress UPR components or activate AMPK. Similarly, natural compounds being found abundantly in vegetables, fruits, herbs, spices, and beans, target UPR components. Caloric restriction and physical exercise confer similar effects on ER stress alleviation and liver diseases management.