Endoplasmic Reticulum Stress in Metabolic Liver Diseases and Hepatic Fibrosis

 

 Permissions and Reprints

Abstract

Endoplasmic reticulum (ER) stress is a major contributor to liver disease and hepatic fibrosis, but the role it plays varies depending on the cause and progression of the disease. Furthermore, ER stress plays a distinct role in hepatocytes versus hepatic stellate cells (HSCs), which adds to the complexity of understanding ER stress and its downstream signaling through the unfolded protein response (UPR) in liver disease. Here, the authors focus on the current literature of ER stress in nonalcoholic and alcoholic fatty liver diseases, how ER stress impacts hepatocyte injury, and the role of ER stress in HSC activation and hepatic fibrosis. This review provides insight into the complex signaling and regulation of the UPR, parallels and distinctions between different liver diseases, and how ER stress may be targeted as an antisteatotic or antifibrotic therapy to limit the progression of liver disease.

• References

• 1 Seitz HK, Bataller R, Cortez-Pinto H. , et al. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4 (01) 16
  CrossrefPubMedGoogle Scholar
• 2 Younossi ZM, Loomba R, Rinella ME. , et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2018; 68 (01) 361-371
  CrossrefPubMedGoogle Scholar
• 3 Yoshiuchi K, Kaneto H, Matsuoka TA. , et al. Pioglitazone reduces ER stress in the liver: direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice. Endocr J 2009; 56 (09) 1103-1111
  CrossrefPubMedGoogle Scholar
• 4 Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147 (02) 943-951
  CrossrefPubMedGoogle Scholar
• 5 Tardif KD, Mori K, Siddiqui A. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 2002; 76 (15) 7453-7459
  CrossrefPubMedGoogle Scholar
• 6 Puri P, Mirshahi F, Cheung O. , et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (02) 568-576
  CrossrefPubMedGoogle Scholar
• 7 Sakon M, Ariyoshi H, Umeshita K, Monden M. Ischemia-reperfusion injury of the liver with special reference to calcium-dependent mechanisms. Surg Today 2002; 32 (01) 1-12
  CrossrefPubMedGoogle Scholar
• 8 Koo JH, Lee HJ, Kim W, Kim SG. Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology 2016; 150 (01) 181.e8-193.e8
  PubMedGoogle Scholar
• 9 Zhang J, Zhang K, Li Z, Guo B. ER stress-induced inflammasome activation contributes to hepatic inflammation and steatosis. J Clin Cell Immunol 2016; 7 (05) 457
  PubMedGoogle Scholar
• 10 Yang F, Wang S, Liu Y. , et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. Free Radic Biol Med 2018; 124: 395-407
  CrossrefPubMedGoogle Scholar
• 11 Wenfeng Z, Yakun W, Di M, Jianping G, Chuanxin W, Chun H. Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease. Ann Hepatol 2014; 13 (05) 489-495
  CrossrefPubMedGoogle Scholar
• 12 Gao J, Jiang Z, Wang S, Zhou Y, Shi X, Feng M. Endoplasmic reticulum stress of Kupffer cells involved in the conversion of natural regulatory T cells to Th17 cells in liver ischemia-reperfusion injury. J Gastroenterol Hepatol 2016; 31 (04) 883-889
  CrossrefPubMedGoogle Scholar
• 13 Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 2008; 29 (03) 317-333
  CrossrefPubMedGoogle Scholar
• 14 Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334 (6059): 1081-1086
  CrossrefPubMedGoogle Scholar
• 15 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
  CrossrefPubMedGoogle Scholar
• 16 Gardner BM, Walter P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 2011; 333 (6051): 1891-1894
  CrossrefPubMedGoogle Scholar
• 17 Wang P, Li J, Tao J, Sha B. The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization. J Biol Chem 2018; 293 (11) 4110-4121
  CrossrefPubMedGoogle Scholar
• 18 Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 2002; 3 (01) 99-111
  CrossrefPubMedGoogle Scholar
• 19 Ali MM, Bagratuni T, Davenport EL. , et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. EMBO J 2011; 30 (05) 894-905
  CrossrefPubMedGoogle Scholar
• 20 Karagöz GE, Acosta-Alvear D, Nguyen HT, Lee CP, Chu F, Walter P. An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 2017; 6: 6
  PubMedGoogle Scholar
• 21 Kopp MC, Nowak PR, Larburu N, Adams CJ, Ali MM. In vitro FRET analysis of IRE1 and BiP association and dissociation upon endoplasmic reticulum stress. eLife 2018; 7: 7
  CrossrefPubMedGoogle Scholar
• 22 McQuiston A, Diehl JA. Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum. F1000 Res 2017; 6: 1897
  CrossrefPubMedGoogle Scholar
• 23 Yang J, Liu H, Li L. , et al. Structural insights into IRE1 functions in the unfolded protein response. Curr Med Chem 2016; 23 (41) 4706-4716
  CrossrefPubMedGoogle Scholar
• 24 Han J, Kaufman RJ. Physiological/pathological ramifications of transcription factors in the unfolded protein response. Genes Dev 2017; 31 (14) 1417-1438
  CrossrefPubMedGoogle Scholar
• 25 Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8 (07) 519-529
  CrossrefPubMedGoogle Scholar
• 26 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
  CrossrefPubMedGoogle Scholar
• 27 Oikawa D, Kimata Y, Kohno K, Iwawaki T. Activation of mammalian IRE1alpha upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins. Exp Cell Res 2009; 315 (15) 2496-2504
  CrossrefPubMedGoogle Scholar
• 28 Kosmaczewski SG, Edwards TJ, Han SM. , et al. The RtcB RNA ligase is an essential component of the metazoan unfolded protein response. EMBO Rep 2014; 15 (12) 1278-1285
  PubMedGoogle Scholar
• 29 Jurkin J, Henkel T, Nielsen AF. , et al. The mammalian tRNA ligase complex mediates splicing of XBP1 mRNA and controls antibody secretion in plasma cells. EMBO J 2014; 33 (24) 2922-2936
  CrossrefPubMedGoogle Scholar
• 30 Lu Y, Liang FX, Wang X. A synthetic biology approach identifies the mammalian UPR RNA ligase RtcB. Mol Cell 2014; 55 (05) 758-770
  CrossrefPubMedGoogle Scholar
• 31 Tirosh B, Iwakoshi NN, Glimcher LH, Ploegh HL. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J Biol Chem 2006; 281 (09) 5852-5860
  CrossrefPubMedGoogle Scholar
• 32 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
  PubMedGoogle Scholar
• 33 Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 2006; 172 (03) 383-393
  CrossrefPubMedGoogle Scholar
• 34 Han D, Lerner AG, Vande Walle L. , et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 2009; 138 (03) 562-575
  CrossrefPubMedGoogle Scholar
• 35 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
  CrossrefPubMedGoogle Scholar
• 36 Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313 (5783): 104-107
  CrossrefPubMedGoogle Scholar
• 37 Upton JP, Wang L, Han D. , et al. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 2012; 338 (6108): 818-822
  CrossrefPubMedGoogle Scholar
• 38 Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 2006; 26 (08) 3071-3084
  CrossrefPubMedGoogle Scholar
• 39 Urano F, Wang X, Bertolotti A. , et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287 (5453): 664-666
  CrossrefPubMedGoogle Scholar
• 40 Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 2003; 100 (05) 2432-2437
  CrossrefPubMedGoogle Scholar
• 41 Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 1999; 19 (12) 8469-8478
  CrossrefPubMedGoogle Scholar
• 42 Darling NJ, Cook SJ. The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. Biochim Biophys Acta 2014; 1843 (10) 2150-2163
  PubMedGoogle Scholar
• 43 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397 (6716): 271-274
  CrossrefPubMedGoogle Scholar
• 44 Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 2004; 101 (31) 11269-11274
  CrossrefPubMedGoogle Scholar
• 45 Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 2004; 167 (01) 27-33
  CrossrefPubMedGoogle Scholar
• 46 Ventoso I, Kochetov A, Montaner D, Dopazo J, Santoyo J. Extensive translatome remodeling during ER stress response in mammalian cells. PLoS One 2012; 7 (05) e35915
  CrossrefPubMedGoogle Scholar
• 47 Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ. Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem J 1999; 339 (Pt 1): 135-141
  PubMedGoogle Scholar
• 48 Zinszner H, Kuroda M, Wang X. , et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998; 12 (07) 982-995
  CrossrefPubMedGoogle Scholar
• 49 Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem 2000; 275 (35) 27013-27020
  CrossrefPubMedGoogle Scholar
• 50 Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 1998; 273 (50) 33741-33749
  CrossrefPubMedGoogle Scholar
• 51 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
  CrossrefPubMedGoogle Scholar
• 52 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
  CrossrefPubMedGoogle Scholar
• 53 Loud AV. A quantitative stereological description of the ultrastructure of normal rat liver parenchymal cells. J Cell Biol 1968; 37 (01) 27-46
  CrossrefPubMedGoogle Scholar
• 54 Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. The compartmentalization of cells. In: Molecular Biology of the Cell. 4th ed. New York, NY: Garland Science; 2002
  Google Scholar
• 55 Barle H, Nyberg B, Essén P. , et al. The synthesis rates of total liver protein and plasma albumin determined simultaneously in vivo in humans. Hepatology 1997; 25 (01) 154-158
  PubMedGoogle Scholar
• 56 Miller LL, Bale WF. Synthesis of all plasma protein fractions except gamma globulins by the liver; the use of zone electrophoresis and lysine-epsilon-C14 to define the plasma proteins synthesized by the isolated perfused liver. J Exp Med 1954; 99 (02) 125-132
  CrossrefPubMedGoogle Scholar
• 57 Fagone P, Jackowski S. Membrane phospholipid synthesis and endoplasmic reticulum function. J Lipid Res 2009; 50 (Suppl): S311-S316
  CrossrefPubMedGoogle Scholar
• 58 Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 2003; 44 (01) 22-32
  CrossrefPubMedGoogle Scholar
• 59 Wang S, Chen Z, Lam V. , et al. IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab 2012; 16 (04) 473-486
  CrossrefPubMedGoogle Scholar
• 60 Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM, Lee AS. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 2011; 54 (01) 229-239
  CrossrefPubMedGoogle Scholar
• 61 Lloyd DJ, Wheeler MC, Gekakis N. A point mutation in Sec61alpha1 leads to diabetes and hepatosteatosis in mice. Diabetes 2010; 59 (02) 460-470
  CrossrefPubMedGoogle Scholar
• 62 Rutkowski DT, Wu J, Back SH. , et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 2008; 15 (06) 829-840
  CrossrefPubMedGoogle Scholar
• 63 Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008; 320 (5882): 1492-1496
  CrossrefPubMedGoogle Scholar
• 64 So JS, Hur KY, Tarrio M. , et al. Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 2012; 16 (04) 487-499
  CrossrefPubMedGoogle Scholar
• 65 Zhang K, Wang S, Malhotra J. , et al. The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 2011; 30 (07) 1357-1375
  CrossrefPubMedGoogle Scholar
• 66 Zeng L, Lu M, Mori K. , et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J 2004; 23 (04) 950-958
  CrossrefPubMedGoogle Scholar
• 67 Gregor MF, Yang L, Fabbrini E. , et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58 (03) 693-700
  CrossrefPubMedGoogle Scholar
• 68 Ozcan U, Cao Q, Yilmaz E. , et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306 (5695): 457-461
  CrossrefPubMedGoogle Scholar
• 69 Yang L, Calay ES, Fan J. , et al. METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 2015; 349 (6247): 500-506
  CrossrefPubMedGoogle Scholar
• 70 Wang JM, Qiu Y, Yang Z. , et al. IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 2018; 11 (530) eaao4617
  CrossrefPubMedGoogle Scholar
• 71 Herrema H, Zhou Y, Zhang D. , et al. XBP1s is an anti-lipogenic protein. J Biol Chem 2016; 291 (33) 17394-17404
  CrossrefPubMedGoogle Scholar
• 72 Mauer AS, Hirsova P, Maiers JL, Shah VH, Malhi H. Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2017; 312 (03) G300-G313
  CrossrefPubMedGoogle Scholar
• 73 Liu X, Henkel AS, LeCuyer BE, Schipma MJ, Anderson KA, Green RM. Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet. Am J Physiol Gastrointest Liver Physiol 2015; 309 (12) G965-G974
  CrossrefPubMedGoogle Scholar
• 74 Lebeaupin C, Vallée D, Rousseau D. , et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology 2018; 68 (02) 515-532
  CrossrefPubMedGoogle Scholar
• 75 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (05) 1343-1351
  CrossrefPubMedGoogle Scholar
• 76 Shan B, Wang X, Wu Y. , et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 2017; 18 (05) 519-529
  CrossrefPubMedGoogle Scholar
• 77 Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 2008; 7 (06) 520-532
  CrossrefPubMedGoogle Scholar
• 78 Li H, Meng Q, Xiao F. , et al. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem J 2011; 438 (02) 283-289
  CrossrefPubMedGoogle Scholar
• 79 Xiao G, Zhang T, Yu S. , et al. ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in mice. J Biol Chem 2013; 288 (35) 25350-25361
  CrossrefPubMedGoogle Scholar
• 80 Cazanave SC, Elmi NA, Akazawa Y, Bronk SF, Mott JL, Gores GJ. CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 2010; 299 (01) G236-G243
  CrossrefPubMedGoogle Scholar
• 81 Cazanave SC, Mott JL, Bronk SF. , et al. Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J Biol Chem 2011; 286 (45) 39336-39348
  CrossrefPubMedGoogle Scholar
• 82 Miyamoto Y, Mauer AS, Kumar S, Mott JL, Malhi H. Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PLoS One 2014; 9 (10) e109637
  CrossrefPubMedGoogle Scholar
• 83 Malhi H, Kropp EM, Clavo VF. , et al. C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. J Biol Chem 2013; 288 (26) 18624-18642
  CrossrefPubMedGoogle Scholar
• 84 Rahman K, Liu Y, Kumar P. , et al. C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. Lab Invest 2016; 96 (08) 895-908
  PubMedGoogle Scholar
• 85 Toriguchi K, Hatano E, Tanabe K. , et al. Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency. J Gastroenterol Hepatol 2014; 29 (05) 1109-1118
  CrossrefPubMedGoogle Scholar
• 86 Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 2010; 298 (05) E1027-E1035
  CrossrefPubMedGoogle Scholar
• 87 Nakagawa H, Umemura A, Taniguchi K. , et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 2014; 26 (03) 331-343
  CrossrefPubMedGoogle Scholar
• 88 Weglarz TC, Degen JL, Sandgren EP. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol 2000; 157 (06) 1963-1974
  CrossrefPubMedGoogle Scholar
• 89 Usui M, Yamaguchi S, Tanji Y. , et al. Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 2012; 61 (08) 1118-1128
  CrossrefPubMedGoogle Scholar
• 90 Fu S, Yang L, Li P. , et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 2011; 473 (7348): 528-531
  PubMedGoogle Scholar
• 91 Mridha AR, Wree A, Robertson AAB. , et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol 2017; 66 (05) 1037-1046
  CrossrefPubMedGoogle Scholar
• 92 Lebeaupin C, Proics E, de Bieville CH. , et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis 2015; 6: e1879
  CrossrefPubMedGoogle Scholar
• 93 Menu P, Mayor A, Zhou R. , et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis 2012; 3: e261
  CrossrefPubMedGoogle Scholar
• 94 Musso G, Cassader M, Paschetta E, Gambino R. Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis. Gastroenterology 2018; 155 (02) 282.e8-302.e8
  PubMedGoogle Scholar
• 95 Volmer R, van der Ploeg K, Ron D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc Natl Acad Sci U S A 2013; 110 (12) 4628-4633
  CrossrefPubMedGoogle Scholar
• 96 Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011; 13 (03) 184-190
  CrossrefPubMedGoogle Scholar
• 97 Rodriguez I, Matsuura K, Khatib K, Reed JC, Nagata S, Vassalli P. A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. J Exp Med 1996; 183 (03) 1031-1036
  CrossrefPubMedGoogle Scholar
• 98 Moravcová A, Červinková Z, Kučera O, Mezera V, Rychtrmoc D, Lotková H. The effect of oleic and palmitic acid on induction of steatosis and cytotoxicity on rat hepatocytes in primary culture. Physiol Res 2015; 64 (Suppl. 05) S627-S636
  PubMedGoogle Scholar
• 99 Listenberger LL, Han X, Lewis SE. , et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003; 100 (06) 3077-3082
  CrossrefPubMedGoogle Scholar
• 100 Akazawa Y, Cazanave S, Mott JL. , et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J Hepatol 2010; 52 (04) 586-593
  CrossrefPubMedGoogle Scholar
• 101 Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 2008; 118 (01) 316-332
  CrossrefPubMedGoogle Scholar
• 102 Lee W-NP, Lim S, Bassilian S, Bergner EA, Edmond J. Fatty acid cycling in human hepatoma cells and the effects of troglitazone. J Biol Chem 1998; 273 (33) 20929-20934
  CrossrefPubMedGoogle Scholar
• 103 Caviglia JM, Gayet C, Ota T. , et al. Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy. J Lipid Res 2011; 52 (09) 1636-1651
  CrossrefPubMedGoogle Scholar
• 104 Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 2006; 291 (02) E275-E281
  CrossrefPubMedGoogle Scholar
• 105 Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 2016; 57 (02) 233-245
  CrossrefPubMedGoogle Scholar
• 106 Dallavilla T, Abrami L, Sandoz PA, Savoglidis G, Hatzimanikatis V, van der Goot FG. Model-driven understanding of palmitoylation dynamics: regulated acylation of the endoplasmic reticulum chaperone calnexin. PLOS Comput Biol 2016; 12 (02) e1004774
  CrossrefPubMedGoogle Scholar
• 107 Lakkaraju AK, Abrami L, Lemmin T. , et al. Palmitoylated calnexin is a key component of the ribosome-translocon complex. EMBO J 2012; 31 (07) 1823-1835
  CrossrefPubMedGoogle Scholar
• 108 Kakisaka K, Cazanave SC, Fingas CD. , et al. Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 2012; 302 (01) G77-G84
  CrossrefPubMedGoogle Scholar
• 109 Han MS, Park SY, Shinzawa K. , et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 2008; 49 (01) 84-97
  CrossrefPubMedGoogle Scholar
• 110 Drzazga A, Sowińska A, Koziołkiewicz M. Lysophosphatidylcholine and lysophosphatidylinosiol--novel promissing signaling molecules and their possible therapeutic activity. Acta Pol Pharm 2014; 71 (06) 887-899
  PubMedGoogle Scholar
• 111 Ojala PJ, Hirvonen TE, Hermansson M, Somerharju P, Parkkinen J. Acyl chain-dependent effect of lysophosphatidylcholine on human neutrophils. J Leukoc Biol 2007; 82 (06) 1501-1509
  CrossrefPubMedGoogle Scholar
• 112 Thibault G, Shui G, Kim W. , et al. The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network. Mol Cell 2012; 48 (01) 16-27
  CrossrefPubMedGoogle Scholar
• 113 Koh JH, Wang L, Beaudoin-Chabot C, Thibault G. Lipid bilayer stress-activated IRE-1 modulates autophagy during endoplasmic reticulum stress. J Cell Sci 2018. DOI: 10.1242/jcs.217992
  PubMedGoogle Scholar
• 114 Barak AJ, Beckenhauer HC, Tuma DJ. Betaine effects on hepatic methionine metabolism elicited by short-term ethanol feeding. Alcohol 1996; 13 (05) 483-486
  CrossrefPubMedGoogle Scholar
• 115 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
  CrossrefPubMedGoogle Scholar
• 116 Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 2003; 124 (05) 1488-1499
  CrossrefPubMedGoogle Scholar
• 117 Fernandez A, Matias N, Fucho R. , et al. ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol 2013; 59 (04) 805-813
  CrossrefPubMedGoogle Scholar
• 118 French SW, Masouminia M, Samadzadeh S, Tillman BC, Mendoza A, French BA. Role of protein quality control failure in alcoholic hepatitis pathogenesis. Biomolecules 2017; 7 (01) E11
  CrossrefPubMedGoogle Scholar
• 119 Jiang JX, Török NJ. Liver injury and the activation of the hepatic myofibroblasts. Curr Pathobiol Rep 2013; 1 (03) 215-223
  CrossrefPubMedGoogle Scholar
• 120 Dorner AJ, Wasley LC, Kaufman RJ. Increased synthesis of secreted proteins induces expression of glucose-regulated proteins in butyrate-treated Chinese hamster ovary cells. J Biol Chem 1989; 264 (34) 20602-20607
  CrossrefPubMedGoogle Scholar
• 121 Hernández-Gea V, Hilscher M, Rozenfeld R. , et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 2013; 59 (01) 98-104
  CrossrefPubMedGoogle Scholar
• 122 Heindryckx F, Binet F, Ponticos M. , et al. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med 2016; 8 (07) 729-744
  CrossrefPubMedGoogle Scholar
• 123 Kim RS, Hasegawa D, Goossens N. , et al. The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy. Sci Rep 2016; 6: 39342
  CrossrefPubMedGoogle Scholar
• 124 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
  CrossrefPubMedGoogle Scholar
• 125 Rutkowski DT, Hegde RS. Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 2010; 189 (05) 783-794
  CrossrefPubMedGoogle Scholar
• 126 de Galarreta MR, Navarro A, Ansorena E. , et al. Unfolded protein response induced by Brefeldin A increases collagen type I levels in hepatic stellate cells through an IRE1α, p38 MAPK and Smad-dependent pathway. Biochim Biophys Acta 2016; 1863 (08) 2115-2123
  PubMedGoogle Scholar
• 127 Wei W, Zhang F, Chen H. , et al. Toxoplasma gondii dense granule protein 15 induces apoptosis in choriocarcinoma JEG-3 cells through endoplasmic reticulum stress. Parasit Vectors 2018; 11 (01) 251
  CrossrefPubMedGoogle Scholar
• 128 Sato H, Shiba Y, Tsuchiya Y, Saito M, Kohno K. 4μ8C inhibits insulin secretion independent of IRE1α RNase activity. Cell Struct Funct 2017; 42 (01) 61-70
  CrossrefPubMedGoogle Scholar
• 129 Huang Y, Li X, Wang Y, Wang H, Huang C, Li J. Endoplasmic reticulum stress-induced hepatic stellate cell apoptosis through calcium-mediated JNK/P38 MAPK and Calpain/Caspase-12 pathways. Mol Cell Biochem 2014; 394 (1–2): 1-12
  CrossrefPubMedGoogle Scholar
• 130 Zhao G, Hatting M, Nevzorova YA. , et al. Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis. Gut 2014; 63 (07) 1159-1172
  CrossrefPubMedGoogle Scholar
• 131 Shih YC, Chen CL, Zhang Y. , et al. Endoplasmic reticulum protein TXNDC5 augments myocardial fibrosis by facilitating extracellular matrix protein folding and redox-sensitive cardiac fibroblast activation. Circ Res 2018; 122 (08) 1052-1068
  CrossrefPubMedGoogle Scholar
• 132 Groenendyk J, Lee D, Jung J. , et al. Inhibition of the unfolded protein response mechanism prevents cardiac fibrosis. PLoS One 2016; 11 (07) e0159682
  CrossrefPubMedGoogle Scholar
• 133 Wang C, Zhang F, Cao Y. , et al. Etoposide induces apoptosis in activated human hepatic stellate cells via ER stress. Sci Rep 2016; 6: 34330
  CrossrefPubMedGoogle Scholar
• 134 Li Y, Chen Y, Huang H. , et al. Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells. Int J Mol Med 2017; 40 (05) 1405-1414
  CrossrefPubMedGoogle Scholar
• 135 He L, Hou X, Fan F, Wu H. Quercetin stimulates mitochondrial apoptosis dependent on activation of endoplasmic reticulum stress in hepatic stellate cells. Pharm Biol 2016; 54 (12) 3237-3243
  CrossrefPubMedGoogle Scholar
• 136 Tsubouchi K, Araya J, Minagawa S. , et al. Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4. Autophagy 2017; 13 (08) 1420-1434
  CrossrefPubMedGoogle Scholar
• 137 Kawamura K, Ichikado K, Yasuda Y, Anan K, Suga M. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm Med 2017; 17 (01) 94
  CrossrefPubMedGoogle Scholar
• 138 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
  CrossrefPubMedGoogle Scholar
• 139 Chang TK, Lawrence DA, Lu M. , et al. Coordination between two branches of the unfolded protein response determines apoptotic cell fate. Mol Cell 2018; 71 (04) 629-636.e5
  CrossrefPubMedGoogle Scholar