The Role of Endoplasmic Reticulum Stress Response in Liver Regeneration

Abstract

Exposure to hepatotoxic chemicals is involved in liver disease–related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post–liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, carbon tetrachloride, acute and chronic alcohol exposure, and physical injury activate the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy–induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in the role of ER stress in injury and regeneration.

Keywords

liver regeneration - ER stress response - unfolded protein response - liver injury - chemical-induced liver injury - partial hepatectomy

Publication History

Accepted Manuscript online:
14 July 2023

Article published online:
18 August 2023

• References

• 1 Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol 2017; 27 (21) R1147-R1151
• 2 Bismuth H. Surgical anatomy and anatomical surgery of the liver. World J Surg 1982; 6 (01) 3-9
• 3 Blouin A, Bolender RP, Weibel ER. Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J Cell Biol 1977; 72 (02) 441-455
• 4 Schulze RJ, Schott MB, Casey CA, Tuma PL, McNiven MA. The cell biology of the hepatocyte: a membrane trafficking machine. J Cell Biol 2019; 218 (07) 2096-2112
• 5 Gunawan BK, Kaplowitz N. Mechanisms of drug-induced liver disease. Clin Liver Dis 2007; 11 (03) 459-475 , v
• 6 Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016; 13 (08) 473-485
• 7 Sala AJ, Bott LC, Morimoto RI. Shaping proteostasis at the cellular, tissue, and organismal level. J Cell Biol 2017; 216 (05) 1231-1241
• 8 Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 2016; 529 (7586): 326-335
• 9 Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8 (07) 519-529
• 10 Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334 (6059): 1081-1086
• 11 Rutkowski DT, Kaufman RJ. That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem Sci 2007; 32 (10) 469-476
• 12 Skullman S, Wirén M, Garlick PJ, McNurlan MA, Larsson J. Protein synthesis in regenerating rat liver during malnutrition. J Hepatol 1994; 21 (02) 174-181
• 13 Dubois V, Gheeraert C, Vankrunkelsven W. et al. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver. Mol Syst Biol 2020; 16 (05) e9156
• 14 Argemí J, Kress TR, Chang HCY. et al. X-box binding protein 1 regulates unfolded protein, acute-phase, and DNA damage responses during regeneration of mouse liver. Gastroenterology 2017; 152 (05) 1203-1216.e15
• 15 Maiers JL, Malhi H. Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis. Semin Liver Dis 2019; 39 (02) 235-248
• 16 Zhou L, Shen H, Li X, Wang H. Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease. Front Immunol 2022; 13 (July): 951406
• 17 Zhang J, Guo J, Yang N, Huang Y, Hu T, Rao C. Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death Dis 2022; 13 (12) 1051
• 18 Vembar SS, Brodsky JL. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 2008; 9 (12) 944-957
• 19 Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 2003; 4 (03) 181-191
• 20 Carrara M, Prischi F, Nowak PR, Kopp MC, Ali MMU. Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling. eLife 2015; 4 (04) 1-16
• 21 Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2 (06) 326-332
• 22 Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A 2005; 102 (52) 18773-18784
• 23 Korennykh A, Walter P. Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol 2012; 28: 251-277
• 24 Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011; 13 (03) 184-190
• 25 Yamamoto K, Sato T, Matsui T. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 2007; 13 (03) 365-376
• 26 Schindler AJ, Schekman R. In vitro reconstitution of ER-stress induced ATF6 transport in COPII vesicles. Proc Natl Acad Sci U S A 2009; 106 (42) 17775-17780
• 27 Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 1999; 10 (11) 3787-3799
• 28 Ye J, Rawson RB, Komuro R. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000; 6 (06) 1355-1364
• 29 Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A 1999; 96 (20) 11041-11048
• 30 You M, Crabb DW. Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. Alcohol 2004; 34 (01) 39-43
• 31 Tam AB, Roberts LS, Chandra V. et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev Cell 2018; 46 (03) 327-343.e7
• 32 Ramdas Nair A, Lakhiani P, Zhang C, Macchi F, Sadler KC. A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver. Genomics 2022; 114 (01) 107-124
• 33 Shuda M, Kondoh N, Imazeki N. et al. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 2003; 38 (05) 605-614
• 34 Cox JS, Shamu CE, Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 1993; 73 (06) 1197-1206
• 35 Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 1998; 12 (12) 1812-1824
• 36 Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 1996; 15 (12) 3028-3039
• 37 Calfon M, Zeng H, Urano F. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002; 415 (6867): 92-96
• 38 Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107 (07) 881-891
• 39 Yoshida H, Oku M, Suzuki M, Mori K. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol 2006; 172 (04) 565-575
• 40 Yoneda T, Imaizumi K, Oono K. et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 2001; 276 (17) 13935-13940
• 41 Han D, Lerner AG, Vande Walle L. et al. IRE1α kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 2009; 138 (03) 562-575
• 42 Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313 (5783): 104-107
• 43 Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009; 186 (03) 323-331
• 44 Dasgupta D, Nakao Y, Mauer AS. et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology 2020; 159 (04) 1487-1503.e17
• 45 Aridor M. A tango for coats and membranes: new insights into ER-to-Golgi traffic. Cell Rep 2022; 38 (03) 110258
• 46 Maiers JL, Kostallari E, Mushref M. et al. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 2017; 65 (03) 983-998
• 47 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397 (6716): 271-274
• 48 Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science 2020; 368 (6489): eaat5314
• 49 Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 2004; 11 (04) 381-389
• 50 Harding HP, Novoa I, Zhang Y. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6 (05) 1099-1108
• 51 Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J Cell Biol 2001; 153 (05) 1011-1022
• 52 Jousse C, Oyadomari S, Novoa I. et al. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J Cell Biol 2003; 163 (04) 767-775
• 53 Palam LR, Baird TD, Wek RC. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem 2011; 286 (13) 10939-10949
• 54 Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov 2022; 21 (02) 115-140
• 55 Li J, Li X, Liu D. et al. Phosphorylation of eIF2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner. Cell Death Dis 2020; 11 (12) 1069
• 56 Song Q, Chen Y, Wang J. et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol 2020; 73 (04) 783-793
• 57 Teske BF, Wek SA, Bunpo P. et al. The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Mol Biol Cell 2011; 22 (22) 4390-4405
• 58 Gonen N, Sabath N, Burge CB, Shalgi R. Widespread PERK-dependent repression of ER targets in response to ER stress. Sci Rep 2019; 9 (01) 4330
• 59 Walter F, Schmid J, Düssmann H, Concannon CG, Prehn JHM. Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival. Cell Death Differ 2015; 22 (09) 1502-1516
• 60 Walter F, O'Brien A, Concannon CG, Düssmann H, Prehn JHM. ER stress signaling has an activating transcription factor 6α (ATF6)-dependent “off-switch”. J Biol Chem 2018; 293 (47) 18270-18284
• 61 Treiman M, Caspersen C, Christensen SB. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases. Trends Pharmacol Sci 1998; 19 (04) 131-135
• 62 Ericson MC, Gafford JT, Elbein AD. Tunicamycin inhibits GlcNAc-lipid formation in plants. J Biol Chem 1977; 252 (21) 7431-7433
• 63 Heifetz A, Keenan RW, Elbein AD. Mechanism of action of tunicamycin on the UDP-GlcNAc:dolichyl-phosphate Glc-NAc-1-phosphate transferase. Biochemistry 1979; 18 (11) 2186-2192
• 64 Bieberich E. Synthesis, processing, and function of N-glycans in N-glycoproteins. Adv Neurobiol 2014; 9: 47-70
• 65 Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol 2011; 490 (C): 71-92
• 66 Foufelle F, Fromenty B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect 2016; 4 (01) e00211
• 67 Jaskulska A, Janecka AE, Gach-Janczak K. Thapsigargin—from traditional medicine to anticancer drug. Int J Mol Sci 2020; 22 (01) 1-12
• 68 Wang X, Xiong W, Tang Y. Tunicamycin suppresses breast cancer cell growth and metastasis via regulation of the protein kinase B/nuclear factor-κB signaling pathway. Oncol Lett 2018; 15 (04) 4137-4142
• 69 You S, Li W, Guan Y. Tunicamycin inhibits colon carcinoma growth and aggressiveness via modulation of the ERK-JNK-mediated AKT/mTOR signaling pathway. Mol Med Rep 2018; 17 (03) 4203-4212
• 70 Goulding LV, Yang J, Jiang Z. et al. Thapsigargin at non-cytotoxic levels induces a potent host antiviral response that blocks influenza a virus replication. Viruses 2020; 12 (10) 1093
• 71 Bhushan B, Apte U. Liver regeneration after acetaminophen hepatotoxicity: mechanisms and therapeutic opportunities. Am J Pathol 2019; 189 (04) 719-729
• 72 Jaeschke H, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 2006; 89 (01) 31-41
• 73 Bajt ML, Cover C, Lemasters JJ, Jaeschke H. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 2006; 94 (01) 217-225
• 74 Chen S, Melchior Jr WB, Guo L. Endoplasmic reticulum stress in drug- and environmental toxicant-induced liver toxicity. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev 2014; 32 (01) 83-104
• 75 Hur KY, So JS, Ruda V. et al. IRE1α activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 2012; 209 (02) 307-318
• 76 Uzi D, Barda L, Scaiewicz V. et al. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 2013; 59 (03) 495-503
• 77 Pumford NR, Roberts DW, Benson RW, Hinson JA. Immunochemical quantitation of 3-(cysteine-S-yl)acetaminophen protein adducts in subcellular liver fractions following a hepatotoxic dose of acetaminophen. Biochem Pharmacol 1990; 40 (03) 573-579
• 78 Weis M, Morgenstern R, Cotgreave IA, Nelson SD, Moldéus P. N-acetyl-p-benzoquinone imine-induced protein thiol modification in isolated rat hepatocytes. Biochem Pharmacol 1992; 43 (07) 1493-1505
• 79 Zhou L, McKenzie BA, Eccleston Jr ED. et al. The covalent binding of [14C]acetaminophen to mouse hepatic microsomal proteins: the specific binding to calreticulin and the two forms of the thiol:protein disulfide oxidoreductases. Chem Res Toxicol 1996; 9 (07) 1176-1182
• 80 Rao PS, Mangipudy RS, Mehendale HM. Tissue injury and repair as parallel and opposing responses to CCl4 hepatotoxicity: a novel dose-response. Toxicology 1997; 118 (2–3): 181-193
• 81 Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007; 117 (03) 539-548
• 82 Iracheta-Vellve A, Petrasek J, Gyongyosi B. et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. J Biol Chem 2016; 291 (52) 26794-26805
• 83 Donohue Jr TM. Alcohol-induced steatosis in liver cells. World J Gastroenterol 2007; 13 (37) 4974-4978
• 84 Dilger K, Metzler J, Bode JC, Klotz U. CYP2E1 activity in patients with alcoholic liver disease. J Hepatol 1997; 27 (06) 1009-1014 . Doi: 1
• 85 Aragon CMG, Rogan F, Amit Z. Ethanol metabolism in rat brain homogenates by a catalase-H₂O₂ system. Biochem Pharmacol 1992; 44 (01) 93-98
• 86 Massey VL, Arteel GE. Acute alcohol-induced liver injury. Front Physiol 2012; 3 (June): 193
• 87 Crabb DW, Liangpunsakul S. Alcohol and lipid metabolism. J Gastroenterol Hepatol 2006; 21 (Suppl. 03) S56-S60
• 88 Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007; 7 (08) 599-612
• 89 Tuma DJ, Hoffman T, Sorrell MF. The chemistry of acetaldehyde-protein adducts. Alcohol Alcohol Suppl 1991; 1: 271-276
• 90 Mueller S, Millonig G, Seitz HK. Alcoholic liver disease and hepatitis C: a frequently underestimated combination. World J Gastroenterol 2009; 15 (28) 3462-3471
• 91 Yuan Y, Tian L, Guo Q. et al. Role of genetic factors in alcoholic liver disease. J Transl Int Med 2019; 7 (02) 51-57
• 92 Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015; 148 (01) 30-36
• 93 O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (01) 307-328
• 94 Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28 (04) 370-379
• 95 Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001; 15 (08) 1335-1349
• 96 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (02) 209-218
• 97 Osna NA, Donohue Jr TM, Kharbanda KK. Alcoholic liver disease: pathogenesis and current management. Alcohol Res 2017; 38 (02) 147-161
• 98 Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2011; 54 (04) 795-809
• 99 Rutkowski DT. Liver function and dysfunction - a unique window into the physiological reach of ER stress and the unfolded protein response. FEBS J 2019; 286 (02) 356-378
• 100 Tsedensodnom O, Vacaru AM, Howarth DL, Yin C, Sadler KC. Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis Model Mech 2013; 6 (05) 1213-1226
• 101 Ji C. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem Res Int 2012; 216450
• 102 Deaciuc IV, Fortunato F, D'Souza NB, Hill DB, McClain CJ. Chronic alcohol exposure of rats exacerbates apoptosis in hepatocytes and sinusoidal endothelial cells. Hepatol Res 2001; 19 (03) 306-324
• 103 Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 2005; 29 (08) 1496-1503
• 104 Magne L, Blanc E, Legrand B. et al. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J Hepatol 2011; 54 (04) 729-737
• 105 Pavitt GD. Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA 2018; 9 (06) e1491
• 106 Michalopoulos GK. Liver regeneration. Liver Biol Pathobiol. 2020; 12: 566-584
• 107 Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021; 18 (01) 40-55
• 108 Clemens MM, McGill MR, Apte U. Mechanisms and Biomarkers of Liver Regeneration after Drug-Induced Liver Injury. Vol 85. 1st ed.. Elsevier Inc.; 2019.
• 109 Apte U, Bhushan B, Dadhania V. Hepatic Defenses against Toxicity: Liver Regeneration and Tissue Repair. Vol 9. 3rd ed.. Elsevier; 2018.
• 110 Liu Y, Shao M, Wu Y. et al. Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses. J Hepatol 2015; 62 (03) 590-598
• 111 Cressman DE, Diamond RH, Taub R. Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology 1995; 21 (05) 1443-1449
• 112 Wang HH, Huang JH, Sue MH. et al. Interleukin-24 protects against liver injury in mouse models. EBioMedicine 2021; 64: 103213
• 113 Wang J, Hu B, Zhao Z. et al. Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver. Cell Death Dis 2020; 11 (01) 17
• 114 Higgins GM, Anderson RM. Experimental pathology of the liver: restoration of the liver of the white rat following partial surgical removal. Arch Pathol (Chic) 1931; 12: 186-202
• 115 Demetriou AA, Reisner A, Sanchez J, Levenson SM, Moscioni AD, Chowdhury JR. Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats. Hepatology 1988; 8 (05) 1006-1009
• 116 Demetris AJ, Kelly DM, Eghtesad B. et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30 (08) 986-993
• 117 Van Thiel DH, Gavaler JS, Kam I. et al. Rapid growth of an intact human liver transplanted into a recipient larger than the donor. Gastroenterology 1987; 93 (06) 1414-1419
• 118 Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H. Liver regeneration in recipients and donors after transplantation. Lancet 1992; 339 (8793): 580-581
• 119 Kam I, Lynch S, Svanas G. et al. Evidence that host size determines liver size: studies in dogs receiving orthotopic liver transplants. Hepatology 1987; 7 (02) 362-366
• 120 Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010; 176 (01) 2-13
• 121 Michalopoulos GK, DeFrances M. Liver regeneration. Adv Biochem Eng Biotechnol 2005; 93 (April): 101-134
• 122 MICHALOPOULOS GK. Liver regeneration. J Cell Physiol 2007; 211 (03) 736-747
• 123 Chen F, Jimenez RJ, Sharma K. et al. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration. Cell Stem Cell 2020; 26 (01) 27-33 -.e4
• 124 Michalopoulos GK. Principles of liver regeneration and growth homeostasis. Compr Physiol 2013; 3 (01) 485-513
• 125 Raven A, Lu WY, Man TY. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 2017; 547 (7663): 350-354
• 126 Lu WY, Bird TG, Boulter L. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17 (08) 971-983
• 127 Choi TY, Ninov N, Stainier DY, Shin D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 2014; 146 (03) 776-788
• 128 Deng X, Zhang X, Li W. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 2018; 23 (01) 114-122.e3
• 129 Kamimoto K, Kaneko K, Kok CY, Okada H, Miyajima A, Itoh T. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. eLife 2016; 5: e15034
• 130 Xie Q, Khaoustov VI, Chung CC. et al. Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. Hepatology 2002; 36 (03) 592-601
• 131 Falasca L, Tisone G, Palmieri G. et al. Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients. Transplantation 2001; 71 (09) 1268-1276
• 132 Vilatoba M, Eckstein C, Bilbao G. et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery 2005; 138 (02) 342-351
• 133 Ben Mosbah I, Alfany-Fernández I, Martel C. et al. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion. Cell Death Dis 2010; 1 (07) e52
• 134 Ben Mosbah I, Duval H, Mbatchi SF. et al. Intermittent selective clamping improves rat liver regeneration by attenuating oxidative and endoplasmic reticulum stress. Cell Death Dis 2014; 5 (03) e1107
• 135 Kolb PS, Ayaub EA, Zhou W, Yum V, Dickhout JG, Ask K. The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis. Int J Biochem Cell Biol 2015; 61: 45-52
• 136 Vang S, Longley K, Steer CJ, Low WC. The unexpected uses of urso- and tauroursodeoxycholic acid in the treatment of non-liver diseases. Glob Adv Health Med 2014; 3 (03) 58-69
• 137 Jia C, Dai C, Bu X. et al. Co-administration of prostaglandin E1 with somatostatin attenuates acute liver damage after massive hepatectomy in rats via inhibition of inflammatory responses, apoptosis and endoplasmic reticulum stress. Int J Mol Med 2013; 31 (02) 416-422
• 138 Gerakis Y, Quintero M, Li H, Hetz C. The UFMylation system in proteostasis and beyond. Trends Cell Biol 2019; 29 (12) 974-986
• 139 Wei Y, Xu X. UFMylation: a unique & fashionable modification for life. Genomics Proteomics Bioinformatics 2016; 14 (03) 140-146
• 140 Sheng L, Li J, Rao S, Yang Z, Huang Y. Cyclin-dependent kinase 5 regulatory subunit associated protein 3: potential functions and implications for development and disease. Front Oncol 2021; 11 (October): 760429
• 141 Yang S, Yang R, Wang H, Huang Y, Jia Y. CDK5RAP3 deficiency restrains liver regeneration after partial hepatectomy triggering endoplasmic reticulum stress. Am J Pathol 2020; 190 (12) 2403-2416
• 142 Lee D, Hokinson D, Park S. et al. ER stress induces cell cycle arrest at the g2/m phase through eIF2α phosphorylation and GADD45α. Int J Mol Sci 2019; 20 (24) 1-13
• 143 Hamanaka RB, Bennett BS, Cullinan SB, Diehl JA. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol Biol Cell 2005; 16 (12) 5493-5501
• 144 Blazanin N, Son J, Craig-Lucas AB. et al. ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras. Proc Natl Acad Sci U S A 2017; 114 (37) 9900-9905
• 145 Pluquet O, Qu LK, Baltzis D, Koromilas AE. Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta. Mol Cell Biol 2005; 25 (21) 9392-9405
• 146 Hong F, Liu B, Wu BX. et al. CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response. Nat Struct Mol Biol 2017; 24 (10) 834-839
• 147 Hong F, Lin CY, Yan J. et al. Canopy Homolog 2 contributes to liver oncogenesis by promoting unfolded protein response-dependent destabilization of tumor protein P53. Hepatology 2022; 76 (06) 1587-1601
• 148 Hart LS, Cunningham JT, Datta T. et al. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest 2012; 122 (12) 4621-4634
• 149 Denoyelle C, Abou-Rjaily G, Bezrookove V. et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat Cell Biol 2006; 8 (10) 1053-1063
• 150 Raffaello A, Mammucari C, Gherardi G, Rizzuto R. Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 2016; 41 (12) 1035-1049
• 151 Vance JE. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta 2014; 1841 (04) 595-609
• 152 Yoboue ED, Sitia R, Simmen T. Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. Cell Death Dis 2018; 9 (03) 331
• 153 Marchi S, Patergnani S, Missiroli S. et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium 2018; 69: 62-72
• 154 Fan Y, Simmen T. Mechanistic connections between endoplasmic reticulum (ER) redox control and mitochondrial metabolism. Cells 2019; 8 (09) 1071
• 155 Rainbolt TK, Saunders JM, Wiseman RL. Stress-responsive regulation of mitochondria through the ER unfolded protein response. Trends Endocrinol Metab 2014; 25 (10) 528-537
• 156 Gutiérrez T, Simmen T. Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. Cell Calcium 2018; 70: 64-75
• 157 Gansemer ER, McCommis KS, Martino M. et al. NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum homeostasis. iScience 2020; 23 (05) 101116
• 158 Ajoolabady A, Kaplowitz N, Lebeaupin C. et al. Endoplasmic reticulum stress in liver diseases. Hepatology 2022; (March): 1-21