|
 
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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 3
| Issue : 2 | Page : 31-37 |
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Endoplasmic reticulum stress response in nonalcoholic fatty liver disease
Arushana Ali1, Kezhong Zhang2
1 Department of Biology and Biochemistry, College of Natural Science and Mathematics, University of Houston, Houston, TX 77004, USA
2 Center for Molecular Medicine and Genetics; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| Date of Submission | 15-Jun-2018 |
| Date of Acceptance | 24-Jun-2018 |
| Date of Web Publication | 12-Jul-2018 |
Correspondence Address:
Arushana Ali
Department of Biology and Biochemistry, College of Natural Science and Mathematics, University of Houston, Houston, TX 77004
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ed.ed_11_18
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased over the past few decades due to a rise in the incidence of Type 2 diabetes and obesity. Sedentary lifestyle coupled with exorbitant consumption of high-caloric diet has been associated with root cause of the epidemic increase in chronic liver diseases. NAFLD is a chronic liver disease which encompasses a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), further leading to irreversible liver cirrhosis. A “multiple hit working model” is a recognized theory that explains the development and progression of NASH, the advanced stage of NAFLD. According to this model, initial hit leads to the development of steatosis, which makes the liver vulnerable to following hits induced by inflammatory cytokines, endotoxins, lipid peroxidation, oxidative stress, endoplasmic reticulum (ER) stress, saturated fatty acid deposition, and/or hepatic organelle dysfunction. These hits eventually result in hepatic fibrosis, inflammation, and apoptosis, which are considered the key features of NASH. Accumulation of hepatic fats leads to the activation of various pathways, including unfolded protein response, which is associated with intracellular stress and inflammation. ER plays a crucial role in restoring cellular homeostasis by directing either through the refolding of misfolded proteins or employing several alternative mechanisms such as ER-associated degradation. ER stress response also causes insulin resistance and inflammation and in the worst cases, culminates in severe liver damage and hepatic cell death, all of which are central to the pathogenesis of NASH. This review sheds some light on recent findings of ER stress response and oxidative stress in the progression of NAFLD.
Keywords: Endoplasmic reticulum, nonalcoholic fatty liver disease, stress response
How to cite this article:
Ali A, Zhang K. Endoplasmic reticulum stress response in nonalcoholic fatty liver disease. Environ Dis 2018;3:31-7 |
| Introduction | |  |
In mammalian cells, endoplasmic reticulum (ER) plays a vital role in biosynthesis of lipids and sterols and is considered a primary cellular site for Ca +2 storage.[1] It provides a unique oxidizing environment for enzymes and chaperones that assist in folding, assembly, and posttranslational modification of proteins. The ER has also evolved a distinctive quality control system that assures the transport of correctly folded proteins out of the ER but retains unfolded or misfolded proteins in the ER. However, pathophysiological stress can lead to the accumulation of misfolded proteins, and thus, ER has evolved a protective mechanism referred to as unfolded protein response (UPR), which senses these misfolded proteins in its lumen and initiates a coordinated response that either refolds the protein or subjects it to degradation.[2],[3],[4] Events that can disrupt the ER protein folding capacity include, but not limited to, buildup of mutant unfolded proteins, a change in redox state, excessive demand for protein synthesis, and calcium depletion. On ER stress, BiP dissociates from ER transmembrane signal transducer, including PKR-like ER kinase (PERK) inositol-requiring enzyme 1 (IRE1), and activates the transcription factor 6 (ATF6), which leads to the activation of subsequent associated UPR signaling pathways. On the release of BiP, PERK dimerizes and self-phosphorylates causing its activation. The activated PERK further phosphorylates the serine residue on the alpha subunit of eukaryotic initiation factor (eIF2α). The activated eIF2α reduces the workload on ER by preventing the binding Met-tRNA to ribosomes thus attenuating translation. In addition, interaction of misfolded or unfolded proteins with IRE1 can also promote its activation. Activated IRE1 splices a 26-basepair intron from X-box binding protein 1 (XBP1) mRNA to produce spliced XBP1 (XBP1s), which encodes a transcription factor required for the upregulation of ER chaperones, and various other genes involved in the process of ER-associated degradation. The disassociation of BiP also permits the translocation of ATF6 to golgi where it is processed into its active form by regulated intramembrane proteolysis. The activated ATF6 can further transactivate UPR target genes such as foldases and molecular chaperones. However, under prolonged or severe stress conditions, ATF4, a downstream effector of PERK-eIF2α pathway, is activated which can induce the expression of pro-apoptotic factor C/EBP homologous protein (CHOP), resulting in apoptotic cell death. Alternatively, the expression of CHOP can also be induced by the spliced XBP-1 which can bind to ER stress response elements (ERSE), ERSE 1 and ERSE2 motifs located in the promoter region of CHOP.[5] For decades, ER stress research, particularly in the context of nonalcoholic fatty liver disease (NAFLD), has gain considerable interest. However, there are quite a lot to unravel regarding the mechanisms and processes by which ER stress signaling contributes to the pathogenesis of NAFLD.[6]
| Endoplasmic Reticulum Stress and Lipid Metabolism | | |
Hepatic steatosis, a relatively benign condition, marks the early manifestation of NAFLD.[6] It is characterized by macrovascular deposition of triglycerides (TGs) in hepatocytes causing liver enlargement. Three important sources through which fatty acids (FAs) are obtained or generated in the liver are dietary sources, lipolysis, or/and de novo lipogenesis. In contrast, reesterification to TG and storing it as lipid droplets, β-oxidation or export of FA as very low-density lipoprotein (VLDL) are some processes through which liver utilizes or shunts the excess FAs. Hence, the hepatic fat accumulation can occur as a consequence of reduced oxidation or export of fat and/or increased synthesis of fat. The previous researches have demonstrated that ER stress can lead to the development of hepatic steatosis by altering the lipid metabolism. It was reported that PERK-eIF2α-ATF4 pathway plays an important role in regulating the process of lipogenesis and hepatic steatosis [Figure 1].[7] Targeted deletion of PERK in mammary epithelium resulted in reduced expression of lipogenic genes and lipogenic enzymes such as stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FAS), and ATP-citrate lyase. It also lead to the growth retardation in suckling pups when fed with milk-containing reducing FAs, due to PERK deletion. It was also reported that when mice fed with high-fat diet were subjected to enforced expression of PPP1R15A, which selectively dephosphorylates eIF2α, showed reduced hepatosteatosis.[8] Subsequently, in these mice, it also resulted in reduced expression of both adipogenic nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and its upstream regulators including CCAAT/enhancer-binding protein-α and-β (C/EBPα, C/EBPβ). In addition, PERK-mediated activation of eIF2α was found to increase the translation of ATF4. Furthermore, ATF4 is important in promoting the expression of lipogenic genes such as sterol regulatory element-binding protein-1c (SREBP-1c), FAS, PPARγ, and acetyl-CoA carboxylase (ACC). Therefore, diminished levels of ATF4 can affect lipid metabolism due to significantly reduced expression of these lipogenic genes in liver and white adipose tissue. Similarly, ATF4-knockout mice were found to be protected from diet-induced obesity and hepatic steatosis due to reduced expression of lipogenic genes.[9] Collectively, these studies imply that lipogenic transcriptional program appears to be regulated by PERK-eIF2α-ATF4 pathway.[10] | Figure 1: The major endoplasmic reticulum -initiated signaling pathways that regulate hepatic lipid metabolism associated with nonalcoholic fatty liver disease
Click here to view |
Another important cell stress transducer ATF6 interacts with SREBPs in modulating the process of lipogenesis [Figure 1].[11] ATF6 and SREBPs are ER membrane-bound transcription factors which are activated by S1P and SP2 cleavage in golgi body, and their activated N-terminus enters the nucleus to induce the expression of genes regulating lipid metabolism and synthesis. At least, one study demonstrated that ATF6 attenuated SREBPs-induced lipogenesis by directly binding to SRE-bound SREBPs and recruiting histone deacetylase-1 which resulted in downregulation of SREBPs-mediated transcriptional activation and lipogenesis. Furthermore, ATF6α knockout mice are prone to develop hepatic steatosis due to reduced FA oxidation.[12] Recent study shows that inhibiting ATF6 suppresses the expression of PPARα, which is involved in transcriptional regulation of various genes associated with β-oxidation of FAs. Thus, when these studies are collectively considered, it suggests that ATF6 is important in modulating the β-oxidation through the activation of PPARα signaling.
Finally, ER-resident sensor IRE1 has also been reported to play an essential role in maintaining hepatic lipid homeostasis under ER stress [Figure 1].[13],[14],[15] The expression levels of two core lipogenic transregulators, C/EBPβ and C/EBPδ, along with the enzymes involved in de novo hepatic TG biosynthesis including SCD1, ACC1, and diacylglycerol acetyltransferase 1 were found to be relatively lower in hepatocyte-specific-IRE1-knockout mice under ER stress induced by tunicamycin (TM) injection. IRE1 also drives C/EBPα expression through activating XBP1 to promote FA oxidation.[16] In addition, IRE1 is also required for the secretion of apolipoprotein B (ApoB) which is essential for transporting TGs and cholesterol in blood stream.[15] IRE1 null mice show increase hepatic ApoB and significantly decrease plasma ApoB after (TM) challenge. This implies that IRE1 is required for efficient TG transfer activity conducted by ApoB proteins. Furthermore, in a recent study performed in ob/ob murine model demonstrated that ER stress slowed down the process of lipogenesis by causing the overexpression of BiP, which further prevented both activations of SREBP-1c, and thus, the expression of SREBP-1c target genes.[17] SREBP-1,2 is an important nuclear transcription factor which transcriptionally activates the genes involved in regulating de novo lipogenesis. Another study has demonstrated that along with SREBP1c, various other lipid synthesis-related genes including ACC, SREBP1c, ACC, GPAT2, GPAT4, and FAS were found to be significantly upregulated as indicated by the increased levels of mRNA.[18] Furthermore, studies have shown the increased level of serum TG and lipid accumulation in liver cells of Sidt2 knockout mice which is consistence with NAFLD occurrence.[19] Although the exact mechanism by which this gene mediates the pathogenesis of NAFLD remains unclear. Several researches performed previously have studied the relationship between the progression of NAFLD and acute ER stress using drugs like TM, to understand and to define the roles of IRE1 in hepatic lipid metabolism. Most recently, an important work showed that, under chronic metabolic stress, for example, after ingesting a high-fat diet, IRE1 is required to maintain lipid homeostasis in the liver by repressing the biogenesis of microRNAs that regulate lipid mobilization.[14] Specifically, the endoribonuclease function of IRE1 in liver is to processed a subset of precursor miRNAs, particularly those belonging to miR-200 and miR-34 families, that target PPARα and the deacetylase sirtuin 1 (SIRT1), two major regulators of FA oxidation and TG lipolysis. Under high-fat diet, IRE1 RNase activity was suppressed by S-nitrosylation of IRE1 protein, leading to upregulation of miR-200 and miR-34 family members and subsequent downregulation of PPARα and SIRT1.[14] As a consequence of decreased FA oxidation and lipolysis in the absence of IRE1, both IRE1-deficient mice and high-fat-fed wild-type mice were vulnerable to NAFLD.
| Endoplasmic Reticulum Stress Response Promotes Apoptosis in Nash | | |
Despite having a very robust and well-coordinated adaptive system, under severe and chronic ER stress conditions, such as those observed in nonalcoholic steatohepatitis (NASH), UPR may fail to restore ER homeostasis. In such circumstances when hepatocytes are injured due to ER and oxidative stress in conjunction with toxic lipid buildup, various apoptotic pathways are activated to induce cell death. IRE1-mediated apoptosis-related kinases/c-Jun N-terminal protein kinases (ASK/JNK) pathway and PERK-mediated eIF2α-CHOP pathway induce cell death by increasing the expression of proapoptotic factors Bax and Bak from Bcl-2 family to promote mitochondrial-dependent cell death.[20] Activated CHOP through PERK-eIF2α pathway also elevates the expression of growth arrest and DNA damage-inducible protein 34 (GADD34) which plays a key function in halting down the repression of general translation which earlier was caused by dephosphorylation of eIF2α. The addendum of newly translated protein results in additional load on ER; thus, eventually leading to chronic activation of UPR which invigorates the process of apoptosis. Research has also shown that the activation of CHOP and activator protein 1 complex (AP-1) ultimately results in mitochondrial dysfunction through upregulating the expression of p53 upregulated modulator of apoptosis which eventually leads to apoptosis.[21] In addition, studies have shown that murine hepatoma cell line treated with saturated fatty acid (SFA) showed increased expression of major ER stress response genes, including GADD34, glucose-regulated protein 78, and CHOP, indicating possible involvement of SFA accumulation in ER stress and mitochondrial-dependent apoptotic cell death.[22] Increasing evidence also suggests that an alternative apoptotic signaling may occur through the binding of IRE1 to tumor necrosis factor (TNF) receptor-associated factor 2 which then activates capcase-12.[23] Several studies have been performed to elucidate the role of caspases and ASK for cell death. Phase II study has demonstrated improved results in ameliorating the symptoms of portal hypertension using a pan-caspase inhibitor, emricasan which is now being investigated to assess its impact on hepatic fibrosis.[24] In addition, ASK-1 inhibitor selonsertib has also shown promising results in a small phase II fibrosis study and is currently under evaluation for NASH with advance fibrosis.[24] In patients with NASH, CK-18 found inside Mallory–Denk bodies is released during the cell death in extracellular space. These cytoplasmic inclusions containing CK-18 serve as a hallmark for pathogenesis of NASH. Stimulator of interferon genes (STING), which is also known as transmembrane protein 173 (TMEM173), is an adapter protein that plays a crucial role in apoptosis through interferon-dependent manner.[25] The previous studies have suggested that STING-IRF3 pathway promotes inflammation in liver cells by activating nuclear factor kappa B (NF-κB) pathway through the phosphorylation of interferon regulatory factor 3 (IRF-3). This pathway subsequently activates mitochondrial apoptosis pathway by interacting with Bcl-2-associated X protein (Bax) on mitochondria which depends on caspases 3 and 9. Studies have shown that STING deficiency prevents the phosphorylation of IRF-3; therefore, the absence of phospho-IRF3 also ceases its interaction with Bax, ultimately preventing the activation of caspases 3 and PARP; thus, causing alleviation of hepatocyte apoptosis.[26]
| Unfolded Protein Response Contributes to Inflammation in Nonalcoholic Steatohepatitis | | |
It was reported that UPR is closely associated with inflammatory response by activating NF-κB.[3] Under normal cellular conditions, the inactivated NF-B is sequestered in the cytoplasm. On receiving an external stimulus, IκB kinase (IKK) phosphorylates two serine residues located in an IκB regulatory domain of NF-B. IKK is a protein complex consisting of two homologous dimers, IKKα, and IKKβ. The activated IKK protein catalyzes the phosphorylation of serine residue on the N-terminal of NF-κB/IκB complex. This leads to rapid dissociation and polyubiquitination of IκB which is eventually followed by its proteasomal degradation. The activated NF-κB upregulates the production of interleukin (IL)-1 β, IL-6, and TNFα. Furthermore, bacterial endotoxin lipopolysaccharide and proinflammatory cytokines IL-1 β, IL-6, and TNFα can induce the activation of liver-specific, ER stress-associated transcription factor CREBH (CAMP-Responsive Element-Binding Protein, hepatocyte-specific) [Figure 1].[27] Once CREBH is activated through regulated intramembrane proteolysis, this activated CREBH can then modulate the hepatic acute-phase response as well as lipid and glucose metabolism.[27],[28],[29] In addition to inflammatory challenges, metabolic energy fluctuations and circadian signals can also regulate CREBH activation or posttranslational modifications.[30],[31],[32],[33] CREBH activation or posttranslational modifications, induced by metabolic signals, represents a critical and regulatory node of energy homeostasis associated with NAFLD and hyperlipidemia.[29],[34] In addition, UPR pathway leads to the activation of IRE1 α which triggers a series of phosphorylation cascade events through binding with adapter protein TNFα receptor-associated factor 2 (TRAF2).[35]
The ultimate consequence of this interaction is to increase the production of proinflammatory cytokines due to the activation of JNK. The two primary isoforms of JNK have specific functions in progression of NASH. Research has indicated that liver injury and cell death events, levels of lipid peroxidation, and expression of proinflammatory genes were significantly lower in JNK1 knockout mice.[36] In contrast, inhibiting the JNK2 leads to altered expression of CHOP and BiP thus leading to increased cell apoptosis. Collectively, this study suggests that both isoforms are functionally different where JNK1 promotes the development of the steatosis and JNK2 prevents hepatocyte cell death. Expression levels of PPARα and PPARγ are inversely associated with the progression of hepatic steatosis and dysregulation of glycogen storage.[37] It is also well known that fibrosis is linked with reduced PPARγ expression which eventually enables the Ito cells (quiescent adipocytes) to activate and differentiate into myofibroblastic hepatic stellate cells. Another important intracellular signaling molecules are calcium and free radicals such as reactive oxygen species (ROS) and nitric oxide (NO). These signaling messengers are primary inflammatory mediators that play an essential role in associating ER stress with inflammation during various metabolic and physiological processes.[38],[39] In addition, research performed on murine models demonstrates that chronic inflammation downregulates the expression of carnitine O-octanoyltransferase, hydroxyacyl-CoA dehydrogenase beta subunit, and carnitine palmitoyl transferase 1A,[40] which plays an important role in β-oxidation of intrahepatocellular FAs and mediating the transport of long-chain FAs. This promotes the progression of NASH due to the imbalance between the de novo FAS and lipid metabolism which exacerbates lipid accumulation in hepatocytes. In addition, research has shown that the reduced levels of G-actin sequestering peptide, Thymosin beta 4 (Tβ4), can be used as a biomarker of liver injury as found in patients with NAFLD.[41] Increased levels of Tβ4 is associated with improved insulin resistance and glucose intolerance. It also exerts anti-inflammatory effects by inhibiting TNF-α-mediated NF-κB pathway.
| Oxidative Stress Induced by Endoplasmic Reticulum Stress in Nonalcoholic Steatohepatitis | | |
Mitochondria are not only a major contributor of intracellular ROS generation but can also be predispose to dysfunction due to a decline in its functionality, as a result of increased imbalance between ROS production and detoxification. Under pathological stress conditions, such as cirrhosis and NASH, the downregulation of PERK-eIF2α-mediated response of NFE2-related factor 2 (NRF2) is associated with mitochondrial dysfunction/depolarization as well as increased hepatic FAs and exacerbation of NASH.[42] The transcription factor NRF2 is activated by the PERK-eIF2α branch of UPR and plays a crucial role in regulating the intermediary metabolism and antioxidant response. Under normal physiological conditions, NRF2 interacts with kelch-like ECH-associated protein 1 (Keap1) which represses the signaling of this transcription factor. However, prooxidant conditions promote the dissociation of NRF2 from Keap1 which then translocates to nucleus and induces the expression of antioxidant responsive element-dependent gene.[43] There are several ER-stress inducing agents such as neurotransmitters, hormones, lipids and cytokines which target calcium release channels such as ryanodine receptor and inositol-1, 4, 5-triphosphate receptor. These stress inducers adversely affect the activities of calcium-dependent protein-folding enzymes by stimulating the release of calcium in cytosol from ER lumen. The increased influx of calcium in cytosol subsequently triggers mitochondrial metabolism to generate ROS. ROS can further impact the function of enzymes involved in protein folding and opening of calcium channels, thus exacerbating the release of calcium which in turn aggravates ER stress response.[3] The ultimate consequence is the accumulation of misfolded proteins, apoptosis, and activation of inflammatory and anti-oxidative pathways promoted by UPR. Furthermore, studies have also shown that prolonged inflammatory stress is linked with lipid accumulation in NASH caused as a result of disruptions in cholesterol efflux and PPAR-LXR-ABCA1/CYP7A1-mediated bile synthesis.[44] Accumulation of excessive amount of NO has also been linked with diabetes and several neurodegenerative diseases such as Parkinson's disease. Along with ROS, NO can also exert its influence on the protein folding mechanisms by inhibiting protein disulfide isomerase, which is an important enzyme required for the formation and isomerization of disulfide bonds in a protein structure.[43] Although intracellular compartments are the major sites of ROS production, recent studies have shown that about 25% of cellular ROS is generated from oxidative folding of reduced proteins. Under normal physiological conditions, cells countervail the ROS production through employing various antioxidant defense systems and also by efficiently stimulating metabolic adaptations that diminishes the substrate supply to the TCA cycle. However, in vitro and in vivo experiments have indicated significantly reduced activity and expression of ROS detoxification mechanisms in NAFLD such as catalase, SOD2, and GSH along with subsequently higher mitochondrial ROS generation.[45] In addition, emerging evidences suggest that the accumulation of unfolded proteins and prolonged ER stress conditions not only triggers the generation of increased levels of ROS but also results in the depletion of intracellular reduced glutathione in ER lumen. Glutathione is an important redox buffer in the lumen of ER as it reduces the improper and unstable disulfide bonds in proteins. Therefore, depletion of glutathione also contributes toward elevated ROS products. Moreover, studies have also shown that increased levels of ROS causes the upregulation of hepatocyte cytochrome CYP2E1 correlated with defective insulin signaling.[46]
| Concluding Remarks | | |
We discussed the recent findings that shed light on the role of ER stress response, inflammatory pathways, and oxidative stress response involved in the pathogenesis of NAFLD. Chronic ER stress disrupts lipid metabolism and homeostasis by reducing the formation and secretion of VLDL as well as by activating the process of lipogenesis. The current treatment standards for the patients with NASH propose changes in sedentary lifestyle through incorporating physical exercise as a preventive measure. Despite many advances made in the field of healthcare and pharmaceuticals, specific mechanisms behind the NAFLD progression remain elusive. The understanding of these signaling pathways is particularly important for designing new therapeutics and interventions that can help modulate the ER stress and inflammatory response. Since oxidative stress is regarded as a key pathological characteristic of NAFLD progression, therefore, a lot of therapeutic approaches involve assessing anti-oxidative drugs to counteract physiological ROS production. Furthermore, taking metabolic and environmental stressors into considerations along with patients' genetic risk variants, therapeutic strategies may need to be customized for the treatment of NAFLD.
Financial support and sponsorship
The research in Dr. Zhang's laboratory was partially supported by National Institutes of Health (NIH) grants DK090313, ES017829 (to KZ), and AR066634 (to KZ). Arushana Ali is an undergraduate student at the University of Houston, who participated in the Summer Undergraduate Research Program in Dr. Zhang's laboratory at the Center for Molecular Medicine and Genetics of Wayne State University School of Medicine.
Conflicts of interest
There are no conflicts of interest.
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