Role of endoplasmic reticulum stress in the pathogenesis of liver failure
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摘要: 肝衰竭的病理过程复杂,病情进展迅速,病死率高,需对其发病机制进行深入研究。早期的,轻度的内质网应激(ERS)可以通过未折叠蛋白反应维持细胞内环境稳定,而持续的、严重的ERS会促进炎症反应及细胞凋亡引起细胞死亡,因此ERS在疾病的发生发展过程中发挥关键作用。主要阐述ERS及其相关信号通路在肝衰竭发病机制中的作用,为肝衰竭的治疗提供新思路。Abstract: Liver failure is a severe liver disease with a complex pathological process, rapid disease progression, and a high mortality rate, and in-depth studies are needed to explore its pathogenesis. Early and mild endoplasmic reticulum stress ( ERS) can maintain the stability of intracellular environment through unfolded protein reaction, while persistent and severe ERS may promote inflammatory response and apoptosis and cause cell death, and therefore, ERS plays a key role in the development and progression of liver failure. This article elaborates on the role of ERS and related signaling pathways in the pathogenesis of liver failure, so as to provides new ideas for the treatment of liver failure.
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Key words:
- endoplasmic reticulum stress /
- liver failure /
- apoptosis /
- inflammation /
- unfolded protein response
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[1] GUZEL E, ARLIER S, GUZELOGLU-KAYISLI O, et al. Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology[J]. Int J Mol Sci, 2017, 18 (4) .pii:E792. [2] PALADE GE. The endoplasmic reticulum[J]. J Biophys Biochem Cytol, 1956, 2 (4 Suppl) :85-98. [3] PALADE GE, SIEKEVITZ P. Liver microsomes; an integrated morphological and biochemical study[J]. J Biophys Biochem Cytol, 1956, 2 (2) :171-200. [4] FALING W, WENYUE L, SVENVAN P, et al. Targeting endoplasmic reticulum stress in liver disease[J]. Expert Rev Gastroenterol Hepatol, 2016, 10 (9) :1041-1052. [5] WANG M, KAUFMAN RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease[J]. Nature, 2016, 529 (7586) :326-335. [6] RON D, WALTER P. Signal integration in the endoplasmic reticulum unfolded protein response[J]. Nat Rev Mol Cell Biol, 2007, 8 (7) :519-529. [7] PLATE L, WISEMAN RL. Regulating secretory proteostasis through the unfolded protein response:From function to therapy[J]. Trends Cell Biol, 2017, 27 (10) :722-737. [8] LPEZ I, TOURNILLON AS, PRADO MARTINS R, et al. p53-mediated suppression of Bi P triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress[J]. Cell Death Differ, 2017, 24 (10) :1717-1729. [9] IURLARO R, MUOZ-PINEDO C. Cell death induced by endoplasmic reticulum stress[J]. FEBS J, 2016, 283 (14) :2640-2652. [10] Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure (2018) [J]. J Clin Hepatol, 2019, 35 (1) :38-44. (in Chinese) 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊治指南 (2018年版) [J].临床肝胆病杂志, 2019, 35 (1) :38-44. [11] CLRIA J, STAUBER RE, COENRAAD MJ, et al. Systemic inflammation in decompensated cirrhosis:Characterization and role in acute-on-chronic liver failure[J]. Hepatology, 2016, 64 (4) :1249-1264. [12] KRAWITZ S, LINGIAH V, PYRSOPOULOS NT. Acute liver failure:Mechanisms of disease and multisystemic involvement[J]. Clin Liver Dis, 2018, 22 (2) :243-256. [13] WU Z, HAN M, CHEN T, et al. Acute liver failure:Mechanisms of immune-mediated liver injury[J]. Liver Int, 2010, 30 (6) :782-794. [14] WU FL, LIU WY, van POUCKE S, et al. Targeting endoplasmic reticulum stress in liver disease[J]. Expert Rev Gastroenterol Hepatol, 2016, 10 (9) :1041-1052. [15] SOLC, SOLE. Update on acute-on-chronic liver failure[J]. Gastroenterol Hepatol, 2018, 41 (1) :43-53. [16] GEHRKE N, HVELMEYER N, WAISMAN A, et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation[J]. J Hepatol, 2018, 68 (5) :986-995. [17] DUVIGNEAU JC, LUS A, GORMAN AM, et al. Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases[J]. Cytokine, 2018, pii:S1043-4666 (18) 30406-X. [18] NISHITOH H, MATSUZAWA A, TOBIUME K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats[J].Genes Dev, 2002, 16 (11) :1345-1355. [19] HAN CY, LIM SW, KOO JH, et al. PHLDA3 overexpression in hepatocytes by endoplasmic reticulum stress via IRE1-Xbp1s pathway expedites liver injury[J]. Gut, 2016, 65 (8) :1377-1388. [20] LEE HY, MARAHATTA A, BHANDARY B, et al. 4-Phenylbutyric acid regulates CCl4-induced acute hepatic dyslipidemia in a mouse model:A mechanism-based PK/PD study[J].Eur J Pharmacol, 2016, 777:104-112. [21] FOUFELLE F, FROMENTY B. Role of endoplasmic reticulum stress in drug-induced toxicity[J]. Pharmacol Res Perspect, 2016, 4 (1) :e00211. [22] LIU R, LI X, HUANG Z, et al. C/EBP homologous protein-induced loss of intestinal epithelial stemness contributes to bile duct ligation-induced cholestatic liver injury in mice[J]. Hepatology, 2018, 67 (4) :1441-1457. [23] KUSAMA H, KON K, IKEJIMA K, et al. Sodium 4-phenylbutyric acid prevents murine acetaminophen hepatotoxicity by minimizing endoplasmic reticulum stress[J]. J Gastroenterol, 2017, 52 (5) :611-622. [24] ZHAO X, ZHOU H, CHENG Y, et al. Reduction in activating transcription factor 4 promotes carbon tetrachloride and lipopolysaccharide/Dgalactosaminemediated liver injury in mice[J]. Mol Med Rep, 2018, 18 (2) :1718-1725. [25] FENG R, HONGBO S, LI Z, et al. The dysregulation of endoplasmic reticulum stress response in acute-on chronic liver failure patients caused by acute exacerbation of chronic hepatitis B[J]. J Viral Hepat, 2016, 23 (1) :23-31. [26] LIYAN C, FENG R, HAIYAN Z, et al. Inhibition of glycogen synthase kinase 3βameliorates D-Gal N/LPS-induced liver injury by reducing endoplasmic reticulum stress-triggered apoptosis[J]. PLo S One, 2012, 7 (9) :e45202. [27] REN F, ZHOU L, ZHANG X, et al. Endoplasmic reticulum stress activated-glycogen synthase kinase 3βaggravates liver inflammation and hepatotoxicity in mice with acute liver failure[J]. Inflammation, 2015, 38 (3) :1151-1165. [28] ZHANG L, REN F, ZHANG X, et al. Peroxisome proliferatoractivated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure[J]. Dis Model Mech, 2016, 9 (7) :799-809. [29] ALICKA M, MARYCZ K. The Effect of chronic inflammation and oxidative and endoplasmic reticulum stress in the course of metabolic syndrome and its therapy[J]. Stem Cells Int, 2018, 2018:4274361. [30] WANG K, LIN B. Pathophysiological significance of hepatic apoptosis[J]. ISRN Hepatol, 2012, 2013:740149. [31] SO JS. Roles of endoplasmic reticulum stress in immune responses[J]. Mol Cells, 2018, 41 (8) :705-716. [32] HU H, TIAN MX, DING C, et al. The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection[J].Front Immunol, 2019, 9:3083. [33] LI ZC, ZHANG LY, GAO MQ, et al. Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2019, 38 (1) :8. [34] KAPHALIA L, BOROUMAND N, HYUNSU J, et al. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding[J]. Toxicol Appl Pharmacol, 2014, 277 (2) :109-117. [35] 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[J]. Science, 2000, 287 (5453) :664-666. [36] MUELLER M, CASTRO RE, THORELL A, et al. Ursodeoxycholic acid:Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients[J].Liver Int, 2018, 38 (3) :523-531. [37] BAHAR E, KIM H, YOON H. ER stress-mediated signaling:action potential and Ca (2+) as key players[J]. Int J Mol Sci, 2016, 17 (9) :1558. [38] BETTIGOLE SE, GLIMCHER LH. Endoplasmic reticulum stress in immunity[J]. Annu Rev Immunol, 2015, 33:107-138. [39] KANEKO M, IMAIZUMI K, SAITO A, et al. ER stress and disease:toward prevention and treatment[J]. Biol Pharm Bull, 2017, 40 (9) :1337-1343. [40] HAN J, KAUFMAN RJ. The role of ER stress in lipid metabolism and lipotoxicity[J]. J Lipid Res, 2016, 57 (8) :1329-1338. [41] YAN M, HUO Y, YIN S, et al. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions[J]. Redox Biol, 2018, 17:274-283. [42] KIM SY, KYAW YY, CHEONG J. Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases[J]. World J Gastroenterol, 2017, 23 (43) :7657-7665. [43] CHOI YM, LEE SY, KIM BJ. Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contribution to the progression of hepatocellular carcinoma[J]. Int J Mol Sci, 2019, 20 (3) . pii:E597.
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