The Dynamic Role of Endoplasmic Reticulum Stress in Chronic Liver Disease

Abstract

Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress-related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR.

Graphical abstract

Figure 1

The signaling pathways of endoplasmic reticulum (ER) stress. The unfolded protein response consists of three main arms/branches, including protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). These pathways are activated by unfolded or misfolded protein accumulation-mediated sequestration of binding-immunoglobulin protein (BiP). Activating these three branches leads to an adaptive recovery response to mitigate the unfolded protein levels and maintain ER homeostasis. Activated endoribonuclease activity of IRE1 promotes cleavage of unspliced X-box binding protein 1 (XBP1u) mRNA to produce spliced XBP1 (XBP1s). XBP1s then promotes the transcription of ER chaperones, ER-associated protein degradation (ERAD) components, and lipid synthesis–associated genes and may induce autophagy. PERK activation promotes the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), forkhead box (FOXO) transcription factors, diacylglycerol (DAG), and the eukaryotic translation initiation factor 2 (eIF2) alpha subunit. Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation promotes preferential activating transcription factor 4 (ATF4) translation. ATF4 transcribes genes associated with amino acid biosynthesis, redox, and autophagy. Activated ATF6 then migrates and is subsequently cleaved at the Golgi apparatus by site-1 and site-2 proteases. ATF6 cleavage liberates the basic leucine zipper-class transcription factor (ATF6-N), which then translocates to the nucleus and transcribes XBP1, ER chaperones, lipid synthesis, and ER expansion genes to restore ER homeostasis and reduce cell stress. These compensatory responses are effective for the short-term mediation of misfolded or unfolded protein levels. However, chronic or excessive unfolded protein response signaling initiates a maladaptive response closely associated with increased cAMP response element-binding (C/EBP) homologous protein (CHOP) protein levels that can lead to apoptosis. DDIT3, DNA damage-inducible transcript 3 protein; JNK, c-Jun N-terminal kinase; RIDD, IRE1-dependent decay of mRNA; TRAF2, tumor necrosis factor receptor–associated factor 2.

Figure 2

The role of endoplasmic reticulum (ER) stress in alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). ALD and NAFLD share common pathologic disease progression, despite having separate disease etiologies. Both excessive caloric intake and alcohol consumption promote ectopic fat distribution in the liver. The hepatic accumulation of lipids alters ER membrane fluidity and induces the accumulation of unfolded proteins in the ER, leading to unfolded protein response (UPR) activation. Although earlier stages of ALD and NAFLD are reversible with abstinence from alcohol or caloric restriction, persistent ER stress activation promotes reactive oxygen species (ROS) formation and pro-inflammatory mediator secretion. These cellular signals promote Kupffer cell activation, liver resident macrophages, and the homing of many peripheral immune cells. In addition, these mediators activate hepatic stellate cells, which increase extracellular matrix deposition when chronically activated, leading to fibrosis. The persistence of ER stress and associated immune and pro-fibrotic responses increases the risk of developing end-stage liver disease and hepatocellular carcinoma (HCC).