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. 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. Chronic liver disease (CLD) affects 1.5 billion individuals worldwide and can lead to complications such as cirrhosis and liver cancers.1Moon A.M. Singal A.G. Tapper E.B. Contemporary epidemiology of chronic liver disease and cirrhosis.Clin Gastroenterol Hepatol. 2020; 18: 2650-2666Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar,2Cheemerla S. Balakrishnan M. Global epidemiology of chronic liver disease.Clin Liver Dis (Hoboken). 2021; 17: 365-370Crossref PubMed Scopus (122) Google Scholar Endoplasmic reticulum (ER) stress is a major contributing factor to the pathogenesis of many CLDs, including hepatic biliary diseases, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC).3Liu X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Crossref PubMed Scopus (71) Google Scholar The ER is responsible for several vital intracellular functions, including calcium homeostasis and steroid hormone and lipid biosynthesis.4Wang M. Kaufman R.J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease.Nature. 2016; 529: 326-335Crossref PubMed Scopus (953) Google Scholar Importantly, the ER is also a key player in the synthesis, folding, trafficking, and degradation of at least one-third of all eukaryotic proteins. Disruption of ER homeostasis creates a unique cellular state termed ER stress. Several physiological or pathological stimuli are identified as ER stress inducers, including ER accumulation of unfolded or misfolded proteins and free cholesterol, depletion of ER calcium stores, oxidative stress, and nutrient deprivation.5Ajoolabady A. Wang S. Kroemer G. Klionsky D.J. Uversky V.N. Sowers J.R. Aslkhodapasandhokmabad H. Bi Y. Ge J. Ren J. ER stress in cardiometabolic diseases: from molecular mechanisms to therapeutics.Endocr Rev. 2021; 42: 839-871Crossref PubMed Scopus (30) Google Scholar ER stress is sensed by the unfolded protein response (UPR), a set of intrinsic signal transduction pathways evolved in mammalian cells. The adaptive UPR reduces unfolded protein load in the ER to maintain cell viability and function. However, extended UPR activation triggers cell death. Recent advances in the UPR field indicate that ER stress–mediated activation of UPR signaling pathways plays a key role in regulating protein folding, lipid metabolism, and the immune response. This review addresses the current understanding ER stress and the UPR signaling cascades and its crucial role in combatting CLD. The ER has a unique intracellular membrane structure, is one of the largest organelles in eukaryotic cells, and is integral for proper cell function.6Wu J. Qiao S. Xiang Y. Cui M. Yao X. Lin R. Zhang X. Endoplasmic reticulum stress: multiple regulatory roles in hepatocellular carcinoma.Biomed Pharmacother. 2021; 142: 112005Crossref PubMed Scopus (22) Google Scholar It has a large dynamic structure with a continuous lumen and membrane. The ER membrane consists of the nuclear envelope and the peripheral ER, defined by its flat sheets and branched tubules. These rough sheets exist in a stacked conformation with luminal thicknesses of 50 nm in mammalian cells.7Schwarz D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (708) Google Scholar The rough ER (RER) has flat sheets studded with ribosomes on the cytosolic surface and is the main location of ER protein synthesis and folding. Conversely, smooth ER (SER) tubules have far fewer membrane-bound ribosomes and appear smooth and highly curved.8Shibata Y. Shemesh T. Prinz W.A. Palazzo A.F. Kozlov M.M. Rapoport T.A. Mechanisms determining the morphology of the peripheral ER.Cell. 2010; 143: 774-788Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar Although the phospholipid composition of the RER and SER is very similar, the SER has twice as much cholesterol as the RER.9Brignac-Huber L.M. Park J.W. Reed J.R. Backes W.L. Cytochrome P450 organization and function are modulated by endoplasmic reticulum phospholipid heterogeneity.Drug Metab Dispos. 2016; 44: 1859-1866Crossref PubMed Scopus (37) Google Scholar The SER smooth tubules are formed by a special class of curvature-stabilizing proteins, reticulon, and factor M. The of the structure and function of the endoplasmic Res. PubMed Scopus Google Scholar are the sheets and tubules in ER also the the in cellular D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (708) Google Scholar cells that large of proteins have an ER structure of RER the cells in lipid synthesis and calcium and ER with have a of SER D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (708) Google Endoplasmic reticulum of cells and its organization into and PubMed Scopus Google Scholar ER that cell a membrane-bound the ER in various biological including protein synthesis, folding, and lipid metabolism, and calcium J. Qiao S. Xiang Y. Cui M. Yao X. Lin R. Zhang X. Endoplasmic reticulum stress: multiple regulatory roles in hepatocellular carcinoma.Biomed Pharmacother. 2021; 142: 112005Crossref PubMed Scopus (22) Google T.A. Protein the eukaryotic endoplasmic reticulum and PubMed Scopus Google and in on the endoplasmic Mol PubMed Scopus Google Full Text Full Text PDF PubMed Scopus Google Scholar Although free ribosomes in the proteins for the all and membrane-bound organelle proteins are on ribosomes in the including proteins to the ER or and D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (708) Google Scholar that to the ER membrane an signal recognized by a signal and are into the ER lumen by the ER M. of the ER Sci. 2020; PubMed Scopus Google Scholar The ER is also responsible for the of of intracellular Zhang Kaufman R.J. and of the unfolded protein Mol 2020; PubMed Scopus Google Scholar and are the ER and organelles such as the and the Endoplasmic reticulum a key in PubMed Scopus (71) Google Scholar The proteins are to the a ER of the that is in tubules and and protein D.S. Blower M.D. The endoplasmic reticulum: structure, function and response to cellular signaling.Cell Mol Life Sci. 2016; 73: 79-94Crossref PubMed Scopus (708) Google A. the PubMed Scopus Google Scholar the ER is the main intracellular calcium and plays an role in calcium of calcium in a review and PubMed Scopus Google A. and for the calcium of PubMed Scopus Google Scholar from ER function due to various physiological or pathologic stimuli to ER stress, has to the progression of several understanding ER stress mechanisms is to and diseases in The UPR is as a response to ER stress and ER stress by ER the have the major UPR signaling ER proteins have identified that regulate the major of the protein endoplasmic reticulum and factor physiological the luminal surface of proteins is by protein also protein is an ER chaperone protein that is as the UPR for all UPR misfolded and unfolded proteins in the ER lumen, to the of proteins, the luminal of the UPR proteins and The unfolded protein and to in the of the endoplasmic 2019; PubMed Scopus Google Scholar the luminal of and are are by and H. endoplasmic reticulum stress by dynamic A. 2010; PubMed Scopus Google J. J. The luminal of the ER stress protein misfolded proteins and triggers Full Text Full Text PDF PubMed Scopus Google Scholar The protein a and on its cytosolic ER stress, misfolded proteins to the luminal surface of and The of the of protein a leading to a that H. T. A. T. is by and by in response to ER stress to a highly Full Text Full Text PDF PubMed Scopus Google Scholar a in is to the and to the adaptive UPR by with ER protein protein folding, and ER-associated degradation the its However, also of the of and several lipid D.S. roles of PubMed Scopus Google Scholar its role in adaptive the cytosolic to the maladaptive UPR by factor factor and protein factor factor and protein and and activation is to However, that also a role in and signaling in PubMed Scopus Google a in cell PubMed Scopus Google Scholar is also a to and a of the eukaryotic factor ER stress, the luminal of to misfolded proteins, leading to and activation J. J. The luminal of the ER stress protein misfolded proteins and triggers Full Text Full Text PDF PubMed Scopus Google Scholar multiple including nuclear factor factor and Y. signaling and cell 2016; PubMed Scopus Google Scholar of by of to the with such as protein and factor A. A. T. of stress response and 2020; PubMed Scopus Google of of an to Full Text Full Text PDF PubMed Scopus Google Scholar activation to cell or H. M. S. The protein factor in endoplasmic reticulum and PubMed Scopus Google Scholar a is a ER stress, from and from the ER to the for that from ER stress, an with M. J. activation of unfolded protein J. 2019; PubMed Scopus Google Scholar to from the cells, has that activation is the of to the for activation The this to in the the of the factor and M. J. activation of unfolded protein J. 2019; PubMed Scopus Google Scholar Although into the mechanisms of the role of in and ER stress is this a role for in and the is by and to the factor J. R. X. R. ER stress of membrane-bound by the that Full Text Full Text PDF PubMed Scopus Google Scholar to the and to ER stress response leading to the of UPR including and in and a that T. T. M. T. H. A. of mammalian ER proteins is by or of and Full Text Full Text PDF PubMed Scopus Google Scholar also lipid synthesis and ER in the of H. S. R. M. S. Kaufman R.J. J.W. of the endoplasmic Sci. PubMed Scopus Google Scholar It that to adaptive of ER stress response such as ER and folding enzymes such as However, is that a role in of stress: in and Sci. PubMed Scopus Google Scholar is a highly cell that cells immune at the cellular Mol PubMed Scopus Google Scholar are responsible for the synthesis and of many proteins, such as and due to the into liver can also lead to UPR activation and this are to ER stress, liver disease X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Crossref PubMed Scopus (71) Google Scholar The UPR to maintain by protein the of misfolded proteins. However, prolonged UPR activation or the of misfolded proteins a from responses to M. mechanisms of and in nonalcoholic fatty liver 2016; Full Text Full Text PDF PubMed Scopus Google Scholar and and the also regulate the of ER stress–mediated of pathways at the activation of Although has to and is recognized for A.M. A. of endoplasmic reticulum PubMed Scopus Google Scholar activation the of the of at the is activation is highly on activation of the factor that can the protein and and X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Crossref PubMed Scopus (71) Google Scholar The cell cell and from cells, nuclear and of cellular of the cellular and membrane and from the This to as the cellular into at the cellular Mol PubMed Scopus Google Scholar this the cells including and that of immune cells and cell that to the cell in cells and the 2016; PubMed Scopus Google Scholar However, by hepatic cells activation and of a of and chronic liver PubMed Scopus Google Scholar Although the is in the is also in ER stress, protein can to the factor factor and and proteins to of the X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Crossref PubMed Scopus (71) Google at the cellular Mol PubMed Scopus Google Scholar This the of and to the the of at the cellular Mol PubMed Scopus Google Scholar the pathways ER stress to cellular such as and regulate of J. M. Lin of cellular homeostasis the unfolded protein 2020; Full Text Full Text PDF PubMed Scopus Google Scholar The that its in to is to lead to can regulate The activation of the of the a that an J. Y. Y. Zhang Y. Wang Y. Y. Y. J. Zhang H. Zhang Wang J. ER-associated liver by multiple PubMed Scopus Google Scholar However, a the at that the accumulation of unfolded proteins and in and J. R. Y. S. Zhang Green R. degradation to ER liver 2021; Full Text Full Text PDF PubMed Scopus Google Scholar These mechanisms to the of in the ER stress response. is an to cells that a to the hepatic can for hepatic However, chronic is maladaptive in the of liver to the of and the of and this has recognized as a factor of disease progression in and chronic liver and nonalcoholic a of and chronic liver PubMed Scopus Google Scholar responses in CLD dynamic the and and immune cells, as as responses in the PubMed Scopus Google Scholar the has an in many ER stress. are protein that a an and The evolved to to various pathologic or physiological including ER stress. are a vital of immune function activation and and are for or cell or cell in the by membrane that for cellular The cell of mechanisms of activation and 2016; PubMed Scopus Google T. activation and a understanding of 2020; PubMed Scopus Google J. and of liver cells in liver PubMed Scopus Google Scholar that ER and activation and and factor X. G. Y. Endoplasmic reticulum stress the and Full Text Full Text PDF PubMed Scopus Google Scholar It has that plays a crucial role in the immune response. ER stress to and activation in human this and activation on mechanisms and with membrane and of membrane J. R. S. M. S. A. A. is in activation stress in the immune Mol Life Sci. PubMed Scopus Google Scholar of human ER stress in and S. R. M. S. X. R. of ER stress in 2021; PubMed Scopus Google Scholar an with ER and Y. A. A. A. G. in cells endoplasmic reticulum stress, and activation in the in 2019; Full Text Full Text PDF PubMed Scopus (30) Google Scholar understanding of the of pathways in liver disease to this review the current that ER stress and the UPR in CLD ER stress has to the progression of various liver diseases, including biliary and CLD can by several from and to and This has in several J. Y. Y. Zhang Y. Wang Y. Y. Y. J. Zhang H. Zhang Wang J. ER-associated liver by multiple PubMed Scopus Google J. Endoplasmic reticulum stress signaling and the pathogenesis of Mol Sci. 2021; PubMed Scopus Google J. M. H. and endoplasmic reticulum stress in hepatocellular PubMed Scopus Google Y. Endoplasmic reticulum stress and the pathogenesis of fatty liver Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar is a CLD in the due to or with diseases have T. H. A. M. Y. Y. Y. A. Y. R. M. of by in with J. 42: PubMed Scopus Google T. Y. T. A. S. T. R. M. intracellular and in PubMed Scopus Google Scholar hepatic in and are with J. Y. J. Y. Y. of in the and progression of liver a 2019; 18: Google Scholar of cell and liver with of key UPR as by X. S. J. Green R.M. of unfolded protein response in liver PubMed Scopus Google Scholar the and pathways with the with also ER stress, leading to in cells in a T. T. H. T. H. The of endoplasmic reticulum stress in hepatocellular PubMed Scopus (37) Google Scholar is a and has that ER stress and cell M. Y. T. S. A. S. liver by of Liver PubMed Scopus Google Scholar and ER stress and to ER stress by the of for protein and Wang Y. from endoplasmic reticulum PubMed Scopus Google R. Endoplasmic reticulum stress in the of liver diseases: of and and Gastroenterol Hepatol. PubMed Scopus Google Scholar with biliary in and key ER stress and of the to ER stress pathways are J. A. A. R. J. A. M. M. J. biliary in and immune PubMed Scopus Google Scholar Several pharmacologic interventions have in reducing ER stress with and to and cell by ER stress, and a cell signaling Y. M. H. and and cell by reducing endoplasmic reticulum stress and oxidative PubMed Scopus Google Scholar has to ER stress, and in S. H. S. hepatic of ER 2020; PubMed Scopus Google Scholar the also inflammation and cell in the of in biliary cirrhosis This also for ER stress–related has to ER protein of and ER stress–mediated cell in cells, and cells from ER stress an cellular protein H. reduces ER stress by regulating of cellular 2016; PubMed Scopus (71) Google Scholar is a by or chronic of that has a from the and liver to in the of hepatic or can a its to contributing to of all and T. S. M. of Liver of liver and from to at the and from the Global of 3: PubMed Scopus Google carcinoma in the of liver Hepatol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar CLDs, potential for have to in the the The of in progression has H. signaling in liver the role of PubMed Scopus Google Scholar ER stress has to pathogenesis in several the and plays an role in pathogenesis by the Y. Wang J. A. ER of to fatty liver Hepatol. 2020; 73: Full Text Full Text PDF PubMed Scopus Google Scholar a of alcoholic ER stress–mediated signaling and and and activation, as by with to ER Y. A. A. A. G. in cells endoplasmic reticulum stress, and activation in the in 2019; Full Text Full Text PDF PubMed Scopus (30) Google Scholar This also that an ER stress–mediated in for and oxidative stress, ER stress, and H. J. H. M. H. J. of chronic on endoplasmic reticulum stress, and oxidative stress in the of Res. 2019; PubMed Scopus Google Scholar ER stress on ER stress and Chronic in the chronic with and ER structure as by and ER stress–related and T. M. M. J.R. accumulation and endoplasmic reticulum stress in chronic PubMed Scopus Google Scholar cells that ER stress, and signaling M. H. X. S. Y. H. R. Bi Y. X. Wang J. cell by endoplasmic reticulum stress and PubMed Scopus Google Scholar ER stress plays a crucial role in and contributing to CLD the at the on and of Liver that chronic from is a molecular and liver the signaling to an for this a potential target for with J. H. R.M. M. Ren T. Y. S. Ren R. S. J. of and 2020; PubMed Google Scholar is the of liver affects to of the including in the S. A. Recent epidemiology of nonalcoholic fatty liver 2021; PubMed Google the public health for a Gastroenterol Hepatol. PubMed Scopus Google Scholar fatty liver disease is with and its prevalence is to of and the public health for a Gastroenterol Hepatol. PubMed Scopus Google Scholar of is with in hepatic lipid ER stress is one of the many that progression from fatty to by the of inflammation and of Y. Endoplasmic reticulum stress and the pathogenesis of fatty liver Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar lipid are into and liver lipid is by from the or in M. mechanisms of and in nonalcoholic fatty liver 2016; Full Text Full Text PDF PubMed Scopus Google Scholar the roles of stress and and signaling in UPR responses in UPR activation is a response to stress, by luminal ER protein However, in ER structure and the this is to lead to of H. The unfolded protein response and hepatic lipid in alcoholic fatty liver 2019; PubMed Scopus Google Scholar Although are of fatty and M. mechanisms of and in nonalcoholic fatty liver 2016; Full Text Full Text PDF PubMed Scopus Google H. The unfolded protein response and hepatic lipid in alcoholic fatty liver 2019; PubMed Scopus Google Scholar by are in Y. Mechanisms of hepatic accumulation in fatty liver PubMed Scopus Google Scholar These many of including and ER homeostasis M. mechanisms of and in nonalcoholic fatty liver 2016; Full Text Full Text PDF PubMed Scopus Google G. A.G. Endoplasmic reticulum stress and in the pathogenesis of fatty liver disease current and 2021; PubMed Scopus Google Scholar fatty ER stress multiple of fatty into the ER membrane membrane M. mechanisms of and in nonalcoholic fatty liver 2016; Full Text Full Text PDF PubMed Scopus Google Scholar to ER membrane are sensed by the of the proteins and leading to UPR H. The unfolded protein response and hepatic lipid in alcoholic fatty liver 2019; PubMed Scopus Google R. G. A. the cell of and by the UPR 2020; PubMed Scopus Google Scholar and is to of the and of the of from the UPR proteins and R. G. A. the cell of and by the UPR 2020; PubMed Scopus Google Scholar in also the of T. S. Green M. T. M. Y. A.M. R.J. and a major of fatty liver Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar the of in Recent has that of in with for and and multiple of liver and inflammation in of and in liver of These that signaling is to liver with of T. of to liver of 2021; PubMed Scopus Google Scholar to the of is to free fatty nuclear factor of cells in a to in with of with with S. R. A. A. H. A. signaling chronic ER stress responses to PubMed Scopus Google Scholar are recognized in of in the of disease progression and the of the ER and S. M. Wang A.M. of a and molecular of of 2021; 73: PubMed Scopus Google Scholar and roles in ER H. and in fatty liver PubMed Scopus Google Scholar have that and are in with and with A. S. S. R. H. M. The and of nonalcoholic is with in PubMed Scopus Google Wang J. H. S. and for fatty liver disease 2021; Full Text Full Text PDF PubMed Scopus Google Y. H. Park T. M. of and nonalcoholic of and 2021; PubMed Scopus Google Scholar These have to in and and signal Y. H. J. R. X. X. G. Zhang G. M. H. The role of in and liver in PubMed Scopus Google Scholar such as and a role in ER stress in The mechanisms by and to fatty liver disease have H. and in fatty liver PubMed Scopus Google Scholar with has also to ER stress in its or in fatty in with the in S. M. A.G. interventions in with fatty liver a review and 2021; PubMed Scopus (30) Google Scholar However, is an to to the of is a hormone that has a to the of potential pharmacologic It in its in pathologic progression is in by ER and stress have in J. M. J. endoplasmic reticulum and in nonalcoholic fatty liver 2020; PubMed Scopus Google T.A. The of the the endoplasmic reticulum stress response and Mol 2021; PubMed Scopus Google Scholar have that hormone and in M. A. J. Y. S. hormone and regulate and PubMed Scopus Google Scholar into the of hormone on ER stress responses is oxidative stress hormone also the cellular of unfolded or misfolded is one of the to of all liver The and with are increasing a worldwide public health J. A. Global of and worldwide for in PubMed Scopus Google Scholar ER stress and J. Qiao S. Xiang Y. Cui M. Yao X. Lin R. Zhang X. Endoplasmic reticulum stress: multiple regulatory roles in hepatocellular carcinoma.Biomed Pharmacother. 2021; 142: 112005Crossref PubMed Scopus (22) Google Scholar ER stress and UPR have as key of Several that major in the UPR are in and to and disease the role of endoplasmic reticulum stress in hepatocellular carcinoma of the human protein 2021; Google Scholar It is that chronic UPR activation and ER stress in cells due to and for protein T. ER stress and inflammation in PubMed Scopus Google Scholar ER stress in cells has also recognized as a key to J. M. H. and endoplasmic reticulum stress in hepatocellular PubMed Scopus Google Scholar alcoholic fatty liver and liver cirrhosis are the main in pathogenesis and J. H. Y. Wang X. J. Yao J. of a for hepatocellular carcinoma on endoplasmic reticulum 2021; PubMed Scopus Google Scholar ER stress plays a role in the progression of and surface can the and in J. Qiao S. Xiang Y. Cui M. Yao X. Lin R. Zhang X. Endoplasmic reticulum stress: multiple regulatory roles in hepatocellular carcinoma.Biomed Pharmacother. 2021; 142: 112005Crossref PubMed Scopus (22) Google Scholar X. R. A. J. J. M. H. of fatty liver and liver in Full Text Full Text PDF PubMed Scopus Google Scholar that the also as factor is in and reducing protein to from to by ER stress. Conversely, the of cells is by a in protein synthesis, leading to UPR activation, in and have also that is responsible for also for and regulating J. M. H. and endoplasmic reticulum stress in hepatocellular PubMed Scopus Google Scholar ER stress to in inflammation and in and disease ER stress as an factor in the of that chronic ER stress is in hepatocellular J. Endoplasmic reticulum stress signaling and the pathogenesis of Mol Sci. 2021; PubMed Scopus Google Scholar However, the role of ER stress in and the of UPR pathways are is a the activation of multiple signaling the molecular and ER stress ER stress and the UPR a role in the pathogenesis of chronic liver on the mechanisms in the ER stress signaling and liver disease progression is vital to pharmacologic are on liver disease and ER stress. in ER stress in in the a of has of ER stress and UPR in several chronic liver diseases, of or has the of potential in and is in this field and lead to the of potential that the progression of several with and the and all of and the

Topics & Concepts